41 results on '"Pascale Lesage"'
Search Results
2. A proteomic screen of Ty1 integrase partners identifies the protein kinase CK2 as a regulator of Ty1 retrotransposition
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Anastasia Barkova, Indranil Adhya, Christine Conesa, Amna Asif-Laidin, Amandine Bonnet, Elise Rabut, Carine Chagneau, Pascale Lesage, and Joël Acker
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Ty1 ,Integrase ,Proteomic ,CK2 protein kinase ,Phosphorylation ,Retrotransposition ,Genetics ,QH426-470 - Abstract
Abstract Background Transposable elements are ubiquitous and play a fundamental role in shaping genomes during evolution. Since excessive transposition can be mutagenic, mechanisms exist in the cells to keep these mobile elements under control. Although many cellular factors regulating the mobility of the retrovirus-like transposon Ty1 in Saccharomyces cerevisiae have been identified in genetic screens, only very few of them interact physically with Ty1 integrase (IN). Results Here, we perform a proteomic screen to establish Ty1 IN interactome. Among the 265 potential interacting partners, we focus our study on the conserved CK2 kinase. We confirm the interaction between IN and CK2, demonstrate that IN is a substrate of CK2 in vitro and identify the modified residues. We find that Ty1 IN is phosphorylated in vivo and that these modifications are dependent in part on CK2. No significant change in Ty1 retromobility could be observed when we introduce phospho-ablative mutations that prevent IN phosphorylation by CK2 in vitro. However, the absence of CK2 holoenzyme results in a strong stimulation of Ty1 retrotransposition, characterized by an increase in Ty1 mRNA and protein levels and a high accumulation of cDNA. Conclusion Our study shows that Ty1 IN is phosphorylated, as observed for retroviral INs and highlights an important role of CK2 in the regulation of Ty1 retrotransposition. In addition, the proteomic approach enabled the identification of many new Ty1 IN interacting partners, whose potential role in the control of Ty1 mobility will be interesting to study.
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- 2022
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3. SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
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Charlotte Martinat, Arthur Cormier, Joëlle Tobaly-Tapiero, Noé Palmic, Nicoletta Casartelli, Bijan Mahboubi, Si’Ana A. Coggins, Julian Buchrieser, Mirjana Persaud, Felipe Diaz-Griffero, Lucile Espert, Guillaume Bossis, Pascale Lesage, Olivier Schwartz, Baek Kim, Florence Margottin-Goguet, Ali Saïb, and Alessia Zamborlini
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Science - Abstract
SAMHD1 is a cellular dNTPase proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting dNTP substrate supply; its anti-viral but not dNTPase function is downregulated by phosphorylation of T592. Here, Martinat et al. describe an additional SUMOylation at residue K595, which promotes the dNTPase-independent restriction activity.
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- 2021
- Full Text
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4. A nuclear pore sub-complex restricts the propagation of Ty retrotransposons by limiting their transcription
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Amandine Bonnet, Carole Chaput, Noé Palmic, Benoit Palancade, and Pascale Lesage
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Genetics ,QH426-470 - Abstract
Beyond their canonical function in nucleocytoplasmic exchanges, nuclear pore complexes (NPCs) regulate the expression of protein-coding genes. Here, we have implemented transcriptomic and molecular methods to specifically address the impact of the NPC on retroelements, which are present in multiple copies in genomes. We report a novel function for the Nup84 complex, a core NPC building block, in specifically restricting the transcription of LTR-retrotransposons in yeast. Nup84 complex-dependent repression impacts both Copia and Gypsy Ty LTR-retrotransposons, all over the S. cerevisiae genome. Mechanistically, the Nup84 complex restricts the transcription of Ty1, the most active yeast retrotransposon, through the tethering of the SUMO-deconjugating enzyme Ulp1 to NPCs. Strikingly, the modest accumulation of Ty1 RNAs caused by Nup84 complex loss-of-function is sufficient to trigger an important increase of Ty1 cDNA levels, resulting in massive Ty1 retrotransposition. Altogether, our study expands our understanding of the complex interactions between retrotransposons and the NPC, and highlights the importance for the cells to keep retrotransposons under tight transcriptional control. Author summary Retroelements, which replicate by reverse transcription of their RNA into a cDNA that is integrated into the host genetic material, play an important role in the plasticity of eukaryotic genomes. The study of yeast retrotransposons has led to the identification of host factors that limit or facilitate retroelement mobility, including components of the nuclear pore complex (NPC), most of them still awaiting mechanistic characterization. Here, we investigated the contribution of the Nup84 complex, a core NPC scaffold, to retrotransposon biology in budding yeast. Our findings uncover that the Nup84 complex restricts the transcription of phylogenetically-distinct Ty retroelements. By focusing on Ty1 retrotransposons, we provide evidence that repression by the Nup84 complex depends on the maintenance at the NPC of the SUMO-protease Ulp1, an essential enzyme of the SUMO pathway with multiple targets in the transcription machinery. We finally show that this transcriptional control is critical for genome dynamics, since a small increase in the accumulation of Ty1 RNAs leads to massive retrotransposition. Our data reveal that although relatively abundant, Ty transcripts are limiting for retrotransposition, underscoring the importance of having their expression tightly controlled. We also characterize a new non-canonical function of NPCs, confirming their connection with genome expression and stability.
- Published
- 2021
5. The invariant arginine within the chromatin-binding motif regulates both nucleolar localization and chromatin binding of Foamy virus Gag
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Joris Paris, Joëlle Tobaly-Tapiero, Marie-Lou Giron, Julien Burlaud-Gaillard, Florence Buseyne, Philippe Roingeard, Pascale Lesage, Alessia Zamborlini, and Ali Saïb
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Foamy virus ,Gag ,Nuclear trafficking ,Nucleolus ,Chromatin-binding ,Post-translational modification ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Nuclear localization of Gag is a property shared by many retroviruses and retrotransposons. The importance of this stage for retroviral replication is still unknown, but studies on the Rous Sarcoma virus indicate that Gag might select the viral RNA genome for packaging in the nucleus. In the case of Foamy viruses, genome encapsidation is mediated by Gag C-terminal domain (CTD), which harbors three clusters of glycine and arginine residues named GR boxes (GRI-III). In this study we investigated how PFV Gag subnuclear distribution might be regulated. Results We show that the isolated GRI and GRIII boxes act as nucleolar localization signals. In contrast, both the entire Gag CTD and the isolated GRII box, which contains the chromatin-binding motif, target the nucleolus exclusively upon mutation of the evolutionary conserved arginine residue at position 540 (R540), which is a key determinant of FV Gag chromatin tethering. We also provide evidence that Gag localizes in the nucleolus during FV replication and uncovered that the viral protein interacts with and is methylated by Protein Arginine Methyltransferase 1 (PRMT1) in a manner that depends on the R540 residue. Finally, we show that PRMT1 depletion by RNA interference induces the concentration of Gag C-terminus in nucleoli. Conclusion Altogether, our findings suggest that methylation by PRMT1 might finely tune the subnuclear distribution of Gag depending on the stage of the FV replication cycle. The role of this step for viral replication remains an open question.
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- 2018
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6. Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
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Alex de Mendoza, Amandine Bonnet, Dulce B. Vargas-Landin, Nanjing Ji, Hongfei Li, Feng Yang, Ling Li, Koichi Hori, Jahnvi Pflueger, Sam Buckberry, Hiroyuki Ohta, Nedeljka Rosic, Pascale Lesage, Senjie Lin, and Ryan Lister
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Science - Abstract
Cytosine methyltransferases (DNMTs) often silence transposons in eukaryotic genomes. Here the authors describe the recurrent acquisition of DNMTs by transposons from two distantly-related eukaryotes and suggest that methylation of CG dinucleotides by transposon DNMTs could modify the host epigenome in dinoflagellates.
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- 2018
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7. International Congress on Transposable elements (ICTE 2016) in Saint Malo: mobile elements under the sun of Brittany
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Pascale Lesage, Mireille Bétermier, Antoine Bridier-Nahmias, Michael Chandler, Séverine Chambeyron, Gael Cristofari, Nicolas Gilbert, Hadi Quesneville, Chantal Vaury, and Jean-Nicolas Volff
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Transposable elements ,Evolution of transposable elements ,Impact on genomes ,Control of transposition ,Mechanism of transposition ,Transposon-based gene therapy ,Genetics ,QH426-470 - Abstract
Abstract The third international conference on Transposable Elements (ICTE) was held 16–19 April 2016 in Saint Malo, France. Organized by the French Transposition Community (Research group of the CNRS: “Mobile genetic elements: from mechanism to populations, an integrative approach”) and the French Society of Genetics, the conference’s goal was to bring together researchers who study transposition in diverse organisms, using multiple experimental approaches. The meeting gathered 180 participants from all around the world. Most of them contributed through poster presentations, invited talks and short talks selected from poster abstracts. The talks were organized into six scientific sessions: “Taming mobile DNA: self and non-self recognition”; “Trans-generational inheritance”; “Mobile DNA genome structure and organization, from molecular mechanisms to applications”; “Remembrance of (retro)transposon past: mobile DNA in genome evolution”; and finally “The yin and the yang of mobile DNA in human health”.
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- 2016
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8. Author Correction: Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
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Alex de Mendoza, Amandine Bonnet, Dulce B. Vargas-Landin, Nanjing Ji, Hongfei Li, Feng Yang, Ling Li, Koichi Hori, Jahnvi Pflueger, Sam Buckberry, Hiroyuki Ohta, Nedeljka Rosic, Pascale Lesage, Senjie Lin, and Ryan Lister
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Science - Abstract
The original version of this Article contained an error in the spelling of the author Hongfei Li, which was incorrectly given as Fei Hong. This has now been corrected in both the PDF and HTML versions of the Article.
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- 2018
- Full Text
- View/download PDF
9. Structural basis of Ty1 integrase tethering to RNA polymerase III for targeted retrotransposon integration
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Phong Quoc Nguyen, Sonia Huecas, Amna Asif-Laidin, Adrián Plaza-Pegueroles, Noé Palmic, Joël Acker, Juan Reguera, Pascale Lesage, and Carlos Fernández-Tornero
- Abstract
SummaryThe yeast Ty1 retrotransposon integrates upstream of genes transcribed by RNA polymerase III (Pol III). Specificity of integration is mediated by an interaction between the Ty1 integrase (IN1) and Pol III, currently uncharacterized at the atomic level. Here, we report cryo-EM structures of Pol III in complex with IN1, revealing a 16-residue segment at the IN1 C-terminus that contacts Pol III subunits AC40 and AC19, an interaction that we validate by in vivo mutational analysis. Unexpectedly, IN1 binding associates with insertion of subunit C11 C-terminal Zn-ribbon into the Pol III funnel, which provides atomic evidence for a two-metal mechanism during RNA cleavage. Moreover, unstructured regions of subunits C53 and C37 reorganize close to C11, likely explaining the connection between the C37/C53 heterodimer and C11 during transcription reinitiation. Our results suggest that IN1 binding induces a Pol III configuration that favors chromatin residence, thus improving the likelihood of Ty1 integration.
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- 2022
10. Entre restriction des éléments transposables et évolution des génomes
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Amandine Bonnet, Pascale Lesage, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut des Sciences de la Terre (ISTerre), and Institut national des sciences de l'Univers (INSU - CNRS)-Institut de recherche pour le développement [IRD] : UR219-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Gustave Eiffel-Université Grenoble Alpes (UGA)
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[SDV]Life Sciences [q-bio] ,General Medicine ,General Biochemistry, Genetics and Molecular Biology ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience; No abstract available
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- 2022
11. A nuclear pore sub-complex restricts the propagation of Ty retrotransposons by limiting their transcription
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Benoit Palancade, Carole Chaput, Pascale Lesage, and Amandine Bonnet
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Transcription (biology) ,Transcriptional regulation ,RNA ,Retrotransposon ,Nuclear pore ,Biology ,Psychological repression ,Genome ,Gene ,Cell biology - Abstract
Beyond their canonical function in nucleocytoplasmic exchanges, nuclear pore complexes (NPCs) regulate the expression of protein-coding genes. Here, we have implemented transcriptomic and molecular methods to specifically address the impact of the NPC on retroelements, which are present in multiple copies in genomes. We report a novel function for the Nup84 complex, a core NPC building block, in specifically restricting the transcription of LTR-retrotransposons in yeast. Nup84 complex-dependent repression impacts bothCopiaandGypsyTy LTR-retrotransposons, all over theS. cerevisiaegenome. Mechanistically, the Nup84 complex restricts the transcription of Ty1, the most active yeast retrotransposon, through the tethering of the SUMO-deconjugating enzyme Ulp1 to NPCs. Strikingly, the modest accumulation of Ty1 RNAs caused by Nup84 complex loss-of-function is sufficient to trigger an important increase of Ty1 cDNA levels, resulting in massive Ty1 retrotransposition. Altogether, our studies expand our understanding of the complex interactions between retrotransposons and the NPC, and highlight the importance for the cells to keep retrotransposon under tight transcriptional control.AUTHOR SUMMARYRetroelements, which replicate by reverse transcription of their RNA into a cDNA that is integrated into the host genetic material, play an important role in the plasticity of eukaryotic genomes. The study of yeast retrotransposons has led to the identification of host factors that limit retroelement mobility, including components of the nuclear pore complex (NPC), most of them still awaiting mechanistic characterization. Here, we investigated the contribution of the Nup84 complex, a core NPC scaffold, to retrotransposon biology in budding yeast. Our findings uncover that the Nup84 complex restricts the transcription of phylogenetically-distinct Ty retroelements. By focusing on Ty1 retrotransposons, we provide evidence that repression by the Nup84 complex depends on the maintenance at the NPC of the SUMO-protease Ulp1, an essential enzyme of the SUMO pathway with multiple targets in the transcription machinery. We finally show that this transcriptional control is critical for genome dynamics, since a small increase in the accumulation of Ty1 RNAs leads to massive retrotransposition. Our data reveal that although relatively abundant, Ty transcripts are limiting for retrotransposition, underscoring the importance of a tight control of their expression. They also characterize a new non-canonical function of NPCs, confirming their connection with genome expression and stability.
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- 2021
12. Eleventh International Foamy Virus Conference—meeting report
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Dirk Lindemann, André F. Santos, Magdalena Materniak-Kornas, Martin Löchelt, Wentao Qiao, Arifa S. Khan, Marcelo A. Soares, Antoine Gessain, Ian A. Taylor, Florence Buseyne, Pascale Lesage, Birgitta M. Wöhrl, Alessia Zamborlini, and Jonathan P. Stoye
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0301 basic medicine ,Model organisms ,foamy virus ,latent infection ,viruses ,Infectious Disease ,Biology ,Eleventh ,Virus ,03 medical and health sciences ,Human health ,Ecology,Evolution & Ethology ,cross-species virus transmission ,Virology ,Animal species ,FV vectors ,virus replication ,Transmission (medicine) ,Retrovirology ,Conference Report ,zoonosis ,restriction factors ,immune responses ,3. Good health ,030104 developmental biology ,Infectious Diseases ,Viral replication ,Genetics & Genomics ,Oncovirus ,Structural Biology & Biophysics - Abstract
The Eleventh International Foamy Virus Conference took place on 9–10 June 2016 at the Institut Pasteur, Paris, France. The meeting reviewed progress on foamy virus (FV) research, as well as related current topics in retrovirology. FVs are complex retroviruses that are widespread in several animal species. Several research topics on these viruses are relevant to human health: cross-species transmission and viral emergence, vectors for gene therapy, development of antiretroviral drugs, retroviral evolution and its influence on the human genome. In this article, we review the conference presentations on these viruses and highlight the major questions to be answered.
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- 2021
- Full Text
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13. Light and shadow on the mechanisms of integration site selection in yeast Ty retrotransposon families
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Pascale Lesage, Amandine Bonnet, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Lesage, Pascale, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Université Paris Cité (UPCité)
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Transposable element ,Retroelements ,Heterochromatin ,Retrotransposon ,Saccharomyces cerevisiae ,Biology ,Genome ,RNA polymerase III ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,Humans ,DNA, Fungal ,Gene ,030304 developmental biology ,0303 health sciences ,030302 biochemistry & molecular biology ,General Medicine ,Chromatin ,chemistry ,Evolutionary biology ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genome, Fungal ,DNA - Abstract
International audience; Transposable elements are ubiquitous in genomes. Their successful expansion depends in part on their sites of integration in their host genome. In Saccharomyces cerevisiae, evolution has selected various strategies to target the five Ty LTR-retrotransposon families into gene-poor regions in a genome, where coding sequences occupy 70% of the DNA. The integration of Ty1/Ty2/Ty4 and Ty3 occurs upstream and at the transcription start site of the genes transcribed by RNA polymerase III, respectively. Ty5 has completely different integration site preferences, targeting heterochromatin regions. Here, we review the history that led to the identification of the cellular tethering factors that play a major role in anchoring Ty retrotransposons to their preferred sites. We also question the involvement of additional factors in the fine-tuning of the integration site selection, with several studies converging towards an importance of the structure and organization of the chromatin.
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- 2021
14. SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
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Noé Palmic, Lucile Espert, Joelle Tobaly-Tapiero, Arthur Cormier, Pascale Lesage, Baek Kim, Olivier Schwartz, Felipe Diaz-Griffero, Florence Margottin, Si'Ana A. Coggins, Charlotte Martinat, Alessia Zamborlini, Mirijana Persaud, Ali Saïb, Julian Buchrieser, Guillaume Bossis, and Nicoletta Casartelli
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Immune system ,Chemistry ,Lysine ,Mutant ,SUMO protein ,Human immunodeficiency virus (HIV) ,medicine ,Phosphorylation ,medicine.disease_cause ,Reverse transcriptase ,SAMHD1 ,Cell biology - Abstract
SAMHD1 is a cellular triphosphohydrolase (dNTPase) proposed to inhibit HIV-1 reverse transcription in non-cycling immune cells by limiting the supply of the dNTP substrates. Yet, phosphorylation of T592 downregulates SAMHD1 antiviral activity, but not its dNTPase function, implying that additional mechanisms contribute to viral restriction. Here, we show that SAMHD1 is SUMOylated on residue K595, a modification that relies on the presence of a proximal SUMO-interacting motif (SIM). Loss of K595 SUMOylation suppresses the restriction activity of SAMHD1, even in the context of the constitutively active phospho-ablative T592A mutant but has no impact on dNTP depletion. Conversely, the artificial fusion of SUMO to a non-SUMOylatable inactive SAMHD1 variant restores its antiviral function. These observations clearly establish that the absence of T592 phosphorylation cannot fully account for the restriction activity of SAMHD1. We find that concomitant SUMOylation of K595 is required to stimulate a dNTPase-independent antiviral activity.
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- 2020
15. Ancrage chromatinien et intégration rétrovirale : implication des protéines IN et Gag
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Guillaume, Beauclair, Aurélie, Tchalikian-Cosson, Antoine, Bridier-Nahmias, Alessia, Zamborlini, Pascale, Lesage, and Ali, Saïb
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Integration into the genome of the host cell is an obligatory step in the replication of retroelements. This feature accounts for the fact that these elements are both potential mutagens as well as vectors suitable for long-term gene therapy. Recently, many studies have reported that proviral insertion is not random but, rather, targets specific regions in the genome. Additionally, it has become clear that this process is highly regulated at the molecular level. Both viral proteins and cellular factors participate in the integration step, explaining why different retroelements have distinct integration profiles. This review describes recent advances about the integration of retroelements, focusing particularly on the mechanisms involved in the selectivity and specificity of integration and the chromatin-anchoring step, which precedes the insertion of the provirus.
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- 2019
16. The Ty1 integrase nuclear localization signal is necessary and sufficient for retrotransposon targeting to tRNA genes
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Noé Palmic, Joël Acker, Pascale Lesage, Christine Conesa, Rachid Menouni, Amandine Bonnet, Hélène Fayol, Camille Grison, Amna Asif-Laidin, and Indranil Adhya
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Transposable element ,0303 health sciences ,biology ,Retrotransposon ,Computational biology ,Ty5 retrotransposon ,Genome ,RNA polymerase III ,Integrase ,03 medical and health sciences ,0302 clinical medicine ,Transfer RNA ,biology.protein ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
SUMMARYIntegration of transposable elements into the genome is mutagenic. Mechanisms that target integration into relatively safe locations and minimize deleterious consequences for cell fitness have emerged during evolution. In budding yeast, the integration of the Ty1 LTR retrotransposon upstream of RNA polymerase III (Pol III)-transcribed genes requires the interaction between the AC40 subunit of Pol III and Ty1 integrase (IN1). Here we show that the IN1-AC40 interaction involves a short linker sequence in the bipartite nuclear localization signal (bNLS) of IN1. Mutations in this sequence do not impact the frequency of Ty1 retromobility, instead they decrease the recruitment of IN1 to Pol III-transcribed genes and the subsequent integration of Ty1 at these loci. The replacement of Ty5 retrotransposon targeting sequence by the IN1 bNLS induces Ty5 integration into Pol III-transcribed genes. Therefore, the IN1 bNLS is both necessary and sufficient to confer integration site specificity on Ty1 and Ty5 retrotransposons.
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- 2019
17. Author Correction: Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
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Hiroyuki Ohta, Alex de Mendoza, Feng Yang, Hongfei Li, Dulce B. Vargas-Landin, Amandine Bonnet, Sam Buckberry, Nedeljka Rosic, Pascale Lesage, Senjie Lin, Ling Li, Nanjing Ji, Ryan Lister, Jahnvi Pflueger, and Koichi Hori
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0303 health sciences ,Multidisciplinary ,Methyltransferase ,Computer science ,Science ,General Physics and Astronomy ,Retrotransposon ,General Chemistry ,Computational biology ,General Biochemistry, Genetics and Molecular Biology ,Spelling ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,lcsh:Q ,lcsh:Science ,030217 neurology & neurosurgery ,Cytosine ,030304 developmental biology - Abstract
The original version of this Article contained an error in the spelling of the author Hongfei Li, which was incorrectly given as Fei Hong. This has now been corrected in both the PDF and HTML versions of the Article.
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- 2018
18. Genome-Wide Mapping of Yeast Retrotransposon Integration Target Sites
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Amna Asif-Laidin, Anastasia Barkova, Pascale Lesage, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex-Institut Universitaire Hématologie-IUH) (IRSL), and Université Paris Diderot - Paris 7 (UPD7)
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0301 basic medicine ,Transposable element ,Genome evolution ,[SDV]Life Sciences [q-bio] ,Saccharomyces cerevisiae ,food and beverages ,Retrotransposon ,Computational biology ,Biology ,biology.organism_classification ,Genome ,DNA sequencing ,Deep sequencing ,03 medical and health sciences ,genomic DNA ,030104 developmental biology ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,ComputingMilieux_MISCELLANEOUS - Abstract
Transposable elements (TEs) are present in virtually all organisms. TE integration into genomes contributes to their structure and evolution, but can also be harmful in some cases. Deciphering where and how TE integration is targeted is fundamental to understand their intricate relationship with their host and explore the outcome of TE mobility on genome evolution and cell fitness. In general, TEs display integration site preference, which differs between elements. High-throughput mapping of de novo insertions by deep sequencing has recently allowed identifying genome-wide integration preferences of several TEs. These studies have provided invaluable clues to address the molecular determinants of integration site preference. Here, we provide a step-by-step methodology to generate massive de novo insertion events and prepare a library of genomic DNA for next-generation sequencing. We also describe a primary bioinformatic procedure to map these insertions in the genome. The whole procedure comes from our recent work on the integration of Ty1 in Saccharomyces cerevisiae, but could be easily adapted to the study of other TEs.
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- 2018
19. Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
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Ling Li, Nanjing Ji, Nedeljka Rosic, Koichi Hori, Hongfei Li, Ryan Lister, Alex de Mendoza, Amandine Bonnet, Sam Buckberry, Dulce B. Vargas-Landin, Pascale Lesage, Senjie Lin, Jahnvi Pflueger, Feng Yang, and Hiroyuki Ohta
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0301 basic medicine ,Methyltransferase ,Retroelements ,Science ,Charophyceae ,General Physics and Astronomy ,Retrotransposon ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Article ,Epigenesis, Genetic ,Evolution, Molecular ,03 medical and health sciences ,chemistry.chemical_compound ,DNA (Cytosine-5-)-Methyltransferases ,Gene Silencing ,lcsh:Science ,Author Correction ,Gene ,Phylogeny ,Epigenomics ,Genetics ,Multidisciplinary ,General Chemistry ,DNA Methylation ,030104 developmental biology ,chemistry ,DNA methylation ,Dinoflagellida ,bacteria ,lcsh:Q ,Cytosine ,DNA - Abstract
Transposable elements are in a constant arms race with the silencing mechanisms of their host genomes. One silencing mechanism commonly used by many eukaryotes is dependent on cytosine methylation, a covalent modification of DNA deposited by C5 cytosine methyltransferases (DNMTs). Here, we report how two distantly related eukaryotic lineages, dinoflagellates and charophytes, have independently incorporated DNMTs into the coding regions of distinct retrotransposon classes. Concomitantly, we show that dinoflagellates of the genus Symbiodinium have evolved cytosine methylation patterns unlike any other eukaryote, with most of the genome methylated at CG dinucleotides. Finally, we demonstrate the ability of retrotransposon DNMTs to methylate CGs de novo, suggesting that retrotransposons could self-methylate retrotranscribed DNA. Together, this is an example of how retrotransposons incorporate host-derived genes involved in DNA methylation. In some cases, this event could have implications for the composition and regulation of the host epigenomic environment., Cytosine methyltransferases (DNMTs) often silence transposons in eukaryotic genomes. Here the authors describe the recurrent acquisition of DNMTs by transposons from two distantly-related eukaryotes and suggest that methylation of CG dinucleotides by transposon DNMTs could modify the host epigenome in dinoflagellates.
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- 2017
20. Integration site selection by retroviruses and transposable elements in eukaryotes
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Tania Sultana, Pascale Lesage, Gaël Cristofari, and Alessia Zamborlini
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0301 basic medicine ,Transposable element ,Genome evolution ,Somatic cell ,Virus Integration ,Computational biology ,Genome, Viral ,Biology ,Genome ,DNA sequencing ,Genome engineering ,Evolution, Molecular ,03 medical and health sciences ,Genetics ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Eukaryota ,Genetic Variation ,Genomics ,Chromatin ,030104 developmental biology ,Retroviridae ,DNA Transposable Elements ,Functional genomics - Abstract
Transposable elements and retroviruses are found in most genomes, can be pathogenic and are widely used as gene-delivery and functional genomics tools. Exploring whether these genetic elements target specific genomic sites for integration and how this preference is achieved is crucial to our understanding of genome evolution, somatic genome plasticity in cancer and ageing, host-parasite interactions and genome engineering applications. High-throughput profiling of integration sites by next-generation sequencing, combined with large-scale genomic data mining and cellular or biochemical approaches, has revealed that the insertions are usually non-random. The DNA sequence, chromatin and nuclear context, and cellular proteins cooperate in guiding integration in eukaryotic genomes, leading to a remarkable diversity of insertion site distribution and evolutionary strategies.
- Published
- 2017
21. International Congress on Transposable elements (ICTE 2016) in Saint Malo: mobile elements under the sun of Brittany
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Mireille Bétermier, Jean-Nicolas Volff, Chantal Vaury, Michael Chandler, Antoine Bridier-Nahmias, Pascale Lesage, Gaël Cristofari, Nicolas Gilbert, Hadi Quesneville, Séverine Chambeyron, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de Recherche Génomique Info (URGI), Institut National de la Recherche Agronomique (INRA), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut Universitaire d'Hématologie ( IUH ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Département chimie alimentation santé environnement risque-CNAM ( CASER ), Laboratoire de microbiologie et génétique moléculaires ( LMGM ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche sur le Cancer et le Vieillissement ( IRCAN ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Saint-Eloi-Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Unité de Recherche Génomique Info ( URGI ), Institut National de la Recherche Agronomique ( INRA ), Génétique, reproduction et développement ( GReD ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR79-Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ), Institut de Génomique Fonctionnelle de Lyon ( IGFL ), École normale supérieure - Lyon ( ENS Lyon ) -Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de microbiologie et génétique moléculaires (LMGM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), Lesage, Pascale, and BMC, BMC
- Subjects
0301 basic medicine ,Transposable element ,lcsh:QH426-470 ,Evolution of transposable elements ,[SDV]Life Sciences [q-bio] ,education ,Control of transposition ,Library science ,Impact on genomes ,Meeting Report ,Biology ,Mobile DNA ,03 medical and health sciences ,Human health ,International congress ,Molecular Biology ,Malo ,ComputingMilieux_MISCELLANEOUS ,Genetics ,[ SDV ] Life Sciences [q-bio] ,Mechanism of transposition ,SAINT ,Genome structure ,biology.organism_classification ,[SDV] Life Sciences [q-bio] ,lcsh:Genetics ,030104 developmental biology ,Transposon-based gene therapy ,Transposable elements ,Mobile genetic elements - Abstract
International audience; AbstractThe third international conference on Transposable Elements (ICTE) was held 16–19 April 2016 in Saint Malo, France. Organized by the French Transposition Community (Research group of the CNRS: “Mobile genetic elements: from mechanism to populations, an integrative approach”) and the French Society of Genetics, the conference’s goal was to bring together researchers who study transposition in diverse organisms, using multiple experimental approaches. The meeting gathered 180 participants from all around the world. Most of them contributed through poster presentations, invited talks and short talks selected from poster abstracts. The talks were organized into six scientific sessions: “Taming mobile DNA: self and non-self recognition”; “Trans-generational inheritance”; “Mobile DNA genome structure and organization, from molecular mechanisms to applications”; “Remembrance of (retro)transposon past: mobile DNA in genome evolution”; and finally “The yin and the yang of mobile DNA in human health”.
- Published
- 2016
22. An RNA polymerase III subunit determines sites of retrotransposon integration
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Amando Flores, Michel Werner, Rachid Menouni, Hélène Fayol, Ali Saïb, Daniel F. Voytas, Antoine Bridier-Nahmias, Joshua A. Baller, Pascale Lesage, Aurélie Tchalikian-Cosson, Agence Nationale de la Recherche (France), Centre National de la Recherche Scientifique (France), European Commission, Ministère de l’Enseignement supérieur et de la Recherche (France), European Molecular Biology Laboratory, Université Paris Diderot, and Institut National de la Santé et de la Recherche Médicale (France)
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Genetics ,Multidisciplinary ,biology ,Gene expression ,Saccharomyces cerevisiae ,biology.protein ,Retrotransposon ,Mobile genetic elements ,biology.organism_classification ,Gene ,Genome ,RNA polymerase III ,Integrase - Abstract
Mobile genetic elements are ubiquitous. Their integration site influences genome stability and gene expression. The Ty1 retrotransposon of the yeast Saccharomyces cerevisiae integrates upstream of RNA polymerase III (Pol III)-transcribed genes, yet the primary determinant of target specificity has remained elusive. Here we describe an interaction between Ty1 integrase and the AC40 subunit of Pol III and demonstrate that AC40 is the predominant determinant targeting Ty1 integration upstream of Pol III-transcribed genes. Lack of an integrase-AC40 interaction dramatically alters target site choice, leading to a redistribution of Ty1 insertions in the genome, mainly to chromosome ends. The mechanism of target specificity allows Ty1 to proliferate and yet minimizes genetic damage to its host., This work was supported by CNRS, INSERM, Université Paris Diderot Sorbonne Paris Cité, Agence nationale de recherches sur le sida et les hépatites virales (grant AO 2008-01), Agence Nationale de la Recherche (grant 13-BSV3-0012-01), and the European Union through the FP7 project HIVINNOV (grant 305137). A.B.-N. was supported by a CNRS Ph.D. fellowship and a European Molecular Biology Organization Short-Term Fellowship (ASTF 17-2013) (to work in D.F.V.’s lab) and A.T.-C. by a Ph.D. fellowship from the Ministère de l’Enseignement Supérieur et de la Recherche.
- Published
- 2015
23. Severe Adenine Starvation Activates Ty1 Transcription and Retrotransposition in Saccharomyces cerevisiae
- Author
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Anne-Laure Todeschini, Mathias Springer, Antonin Morillon, and Pascale Lesage
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DNA, Complementary ,Saccharomyces cerevisiae Proteins ,Retroelements ,Transcription, Genetic ,Gene Expression ,Retrotransposon ,RNA polymerase II ,Saccharomyces cerevisiae ,chemistry.chemical_compound ,Transcription (biology) ,RNA polymerase ,RNA, Messenger ,Molecular Biology ,Gene ,Transcription factor ,Adenosine Triphosphatases ,Genetics ,biology ,Adenine ,Promoter ,Cell Biology ,Adenosine Monophosphate ,Long terminal repeat ,DNA-Binding Proteins ,chemistry ,Mutation ,Trans-Activators ,biology.protein ,Transcription Factors - Abstract
Retrotransposons are a class of mobile genetic elements that replicate through an RNA intermediate and resemble retroviruses from many points of view. Five different families of retrotransposons (Ty1 to Ty5) have been identified in the genome of the yeast Saccharomyces cerevisiae (reviewed in references 31, 48, and 57). They all share the same basic structure, consisting of two direct long terminal repeats (LTR) flanking the TYA and TYB open reading frames, which are analogous to the retroviral gag and pol genes. Ty1 is the most abundant of the retrotransposon families, with around 30 copies per haploid genome, and is a model for LTR-containing elements. Ty1 is transcribed from LTR to LTR by RNA polymerase II, with the resulting transcript serving as a template for both translation and reverse transcription. Translation leads to the synthesis of Ty1Ap, the structural component of the virus-like particle and of the Ty1A-Ty1B polyprotein containing protease (PR), integrase (IN), reverse transcriptase (RT), and RNase H (RH) catalytic domains, all of which are essential for retrotransposition. The linear double-stranded cDNA molecule, produced by reverse transcription within the virus-like particle, enters the genome either by integrase-mediated integration or, to a lesser extent, by homologous recombination with genomic elements. Ty1 preferentially integrates next to RNA polymerase III-dependent promoters, but less frequent insertions into, or upstream of, genes transcribed by RNA polymerase II have been reported. In these cases, Ty1 insertions have been shown to alter the expression of the neighboring genes by activating or inactivating them or by importing new regulatory mechanisms on their expression. Such insertions may provide a means of evolution to the yeast genome. The Ty1 element and its host have evolved numerous control systems that keep retrotransposition at a low level, yet allowing it to be activated under stress (10, 31, 57). In contrast to the host defense, which acts mainly at the posttranscriptional level, the Ty1 response to stress generally involves activation of transcription. The promoter of Ty1 is complex, and its structure is very similar to that of higher eukaryotes. It extends over 1 kb, both upstream and downstream of two TATA boxes, and includes the 5′ LTR and part of the TY1A open reading frame. At least eight transcription factors (Gcr1, Ste12, Tec1, Mcm1, Tea1, Rap1, Gcn4, and Mot3), which bind to the Ty1 promoter (15, 16, 21, 22, 29, 33, 36, 37, 56), and three chromatin-remodeling complexes (Swi/Snf, SAGA, and ISWI) regulate Ty1 transcription in haploid cells (7, 20, 24, 28, 42). The activation of Ty1 transcription by the invasive/filamentous pathway in response to environmental signals, such as nitrogen starvation, occurs through the transcriptional activators Ste12 and Tec1 (9, 37). These proteins recognize a sequence called FRE (filamentous responsive element), located in TY1A sequences downstream of the TATA boxes of the Ty1 promoter (2). In addition to their role in Ty1 activation by the invasive/filamentous signaling pathway, Ste12 and Tec1 are important for basal levels of Ty1 transcription in haploid cells (29, 37). Exposure of yeast cells to DNA-damaging agents also increases Ty transcript levels and activates Ty retrotransposition (5, 35, 44, 47, 53). The mechanism of transcriptional activation by DNA damage has not been elucidated, however. Insights into the transcription of individual Ty1 elements have recently been obtained using a set of haploid strains, each expressing lacZ from the transcription control signals of a specific Ty1 element at its native location. This set of 31 strains allows study of the transcription of all but one of the Ty1 elements present in the genome of S288C (36). The comparison of lacZ expression in these strains identified two basic classes of Ty1 elements according to their level of expression: weakly and highly expressed elements. Based on genetic data, it was proposed that repression of transcription of the highly expressed Ty1 elements by chromatin structures is antagonized by Swi/Snf and SAGA. In addition, several endogenous Ty1 elements, mostly those expressed at high levels, contain five potential Gcn4 binding sites in their 5′ LTR (36). Gcn4 is a transcriptional activator that binds to multiple sites upstream of amino acid biosynthetic genes (25). The transcription of the highly expressed Ty1 elements depends on GCN4 in the absence of amino acids and is activated when GCN4 is overexpressed. The Bas1 transcriptional activator recognizes a DNA sequence (TGACTC) (13, 55) similar to the Gcn4 binding site [TGA(C/G)TCA] (39). The difference is that an A nucleotide is generally present at the 3′ extremity of Gcn4 binding sites but is never found in Bas1 binding sites. All but one of the Gcn4 binding sites located in Ty1 elements contain a T nucleotide at the last position and could be recognized by Bas1, suggesting that Bas1 could potentially activate Ty1 transcription. Bas1, together with Bas2, is required for the regulated activation of the ADE genes of the de novo AMP biosynthesis pathway (13). When adenine is provided in the environment, it enters the yeast cells and is converted to AMP and then to other adenine nucleotides. In the absence of purines, Bas1 and Bas2 interact to activate the ADE genes (40, 60). Since the Gcn4 binding sites located in Ty1 were potentially recognized by Bas1, we asked whether Ty1 transcription was stimulated under conditions of adenine starvation. We discovered that although Bas1 does not activate Ty1 transcription, severe adenine starvation does. Our results indicate that activation occurs mainly on poorly expressed elements, whose transcription is repressed by chromatin. We also show that the activation of transcription of individual Ty1 elements under severe adenine starvation correlates with a proportional increase in their retrotransposition. Finally, we provide evidence that the activation mechanism requires chromatin remodeling at Ty1 promoters.
- Published
- 2005
24. Happy together: the life and times of Ty retrotransposons and their hosts
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Anne-Laure Todeschini and Pascale Lesage
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Genetics ,Models, Genetic ,Retroelements ,Transcription, Genetic ,biology ,Host (biology) ,Saccharomyces cerevisiae ,food and beverages ,Retrotransposon ,biology.organism_classification ,Yeast ,Evolution, Molecular ,Molecular Biology ,Genetics (clinical) - Abstract
The aim of this review is to describe the level of intimacy between Ty retrotransposons (Ty1–Ty5) and their host the yeast Saccharomyces cerevisiae. The effects of Ty location in the genome and of host proteins on the expression and mobility of Ty elements are highlighted. After a brief overview of Ty diversity and evolution, we describe the factors that dictate Ty target-site preference and the impact of targeting on Ty and adjacent gene expression. Studies on Ty3 and Ty5 have been especially informative in unraveling the role of host factors (Pol III machinery and silencing proteins, respectively) and integrase in controlling the specificity of integration. In contrast, not much is known regarding Ty1, Ty2 and Ty4, except that their insertion depends on the transcriptional competence of the adjacent Pol III gene and might be influenced by some chromatin components. This review also brings together recent findings on the regulation of Ty1 retrotransposition. A large number of host proteins (over 30) involved in a wide range of cellular processes controls either directly or indirectly Ty1 mobility, primarily at post-transcriptional steps. We focus on several genes for which more detailed analyses have permitted the elaboration of regulatory models. In addition, this review describes new data revealing that repression of Ty1 mobility also involves two forms of copy number control that act at both the trancriptional and post-transcriptional levels. Since S. cerevisiae lacks the conserved pathways for copy number control via transcriptional and post-transcriptional gene silencing found in other eukaryotes, Ty1 copy number control must be via another mechanism whose features are outlined. Ty1 response to stress also implicates activation at both transcriptional and postranscriptional steps of Ty1. Finally, we provide several insights in the role of Ty elements in chromosome evolution and yeast adaptation and discuss the factors that might limit Ty ectopic recombination.
- Published
- 2005
25. Strains isogenic to S288C used in the Yeast Genome Sequencing Programme carry a functional KSS1 gene
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Mathias Springer, Antonin Morillon, and Pascale Lesage
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Genetics ,Regulation of gene expression ,Saccharomyces cerevisiae Proteins ,Genotype ,MAPKAPK2 ,Molecular Sequence Data ,Mutant ,Saccharomyces cerevisiae ,General Medicine ,Biology ,biology.organism_classification ,Pheromones ,Recombinant Proteins ,Fungal Proteins ,Amino Acid Substitution ,Fus3 ,Mutagenesis, Site-Directed ,Amino Acid Sequence ,Genome, Fungal ,Mitogen-Activated Protein Kinases ,Signal transduction ,Cyclin-dependent kinase 7 ,Gene - Abstract
In Saccharomyces cerevisiae, the KSS1 gene encodes the MAP kinase of the invasive/filamentous growth pathway. In addition to its role in this signal transduction pathway, Kssl can replace the Fus3 MAP kinase in the pheromone-response pathway, in the absence of FUS3. Previous work indicated that derivatives of the S288C strain carry a mutant kss1 allele. Here, we report evidence that S288C derivatives used in the Yeast Genome Sequencing Programme carry a functional KSS1 gene and can thus be used to study the regulation of gene expression by KSS1.
- Published
- 2001
26. Two large-scale analyses of Ty1 LTRretrotransposon de novo insertion events indicate that Ty1 targets nucleosomal DNA near the H2A/H2B interface
- Author
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Pascale Lesage, Antoine Bridier-Nahmias, Pathologie et virologie moléculaire (PVM (UMR_7151)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A B-N is supported by a graduate student fellowship from the CNRS (bourse des ingénieurs). Work in the laboratory of PL is supported by the French National Research Agency against AIDS (ANRS) and intramural fundings from CNRS and INSERM., BMC, Ed., and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)
- Subjects
lcsh:QH426-470 ,LTR retrotransposon ,Retrotransposon ,Computational biology ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Biology ,RNA polymerase III ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Transcription (biology) ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Selective integration ,Molecular Biology ,Gene ,Large-scale analysis ,030304 developmental biology ,Genetics ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Ty1 ,lcsh:Genetics ,chemistry ,Commentary ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Developmental biology ,030217 neurology & neurosurgery ,DNA - Abstract
Background Over the years, a number of reports have revealed that Ty1 integration occurs in a 1-kb window upstream of Pol III-transcribed genes with an approximate 80-bp periodicity between each integration hotspot and that this targeting requires active Pol III transcription at the site of integration. However, the molecular bases of Ty1 targeting are still not understood. Findings The publications by Baller et al. and Mularoni et al. in the April issue of Genome Res. report the first high-throughput sequencing analysis of Ty1 de novo insertion events. Their observations converge to the same conclusion, that Ty1 targets a specific surface of the nucleosome at he H2A/H2B interface. Conclusion This discovery is important, and should help identifying factor(s) involved in Ty1 targeting. Recent data on transposable elements and retroviruses integration site choice obtained by large-scale analyses indicate that transcription and chromatin structure play an important role in this process. The studies reported in this commentary add a new evidence of the importance of chromatin in integration selectivity that should be of interest for everyone interested in transposable elements integration.
- Published
- 2012
27. Tye7 regulates yeast Ty1 retrotransposon sense and antisense transcription in response to adenylic nucleotides stress
- Author
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Benoît Pinson, Hélène Fayol, Aurélie Tchalikian-Cosson, Carole Pennetier, Géraldine Servant, Fanny Coulpier, Sophie Lemoine, Antoine Bridier-Nahmias, Bertrand Daignan-Fornier, Anne-Laure Todeschini, Pascale Lesage, Service de Physique Théorique (SPhT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Pathologie et virologie moléculaire (PVM (UMR_7151)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Todeschini, Anne-Laure, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Transcriptional Activation ,Transposable element ,Saccharomyces cerevisiae Proteins ,Retroelements ,[SDV]Life Sciences [q-bio] ,Response element ,Retrotransposon ,Saccharomyces cerevisiae ,Gene Regulation, Chromatin and Epigenetics ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Adenosine Triphosphate ,Stress, Physiological ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Sense (molecular biology) ,Genetics ,RNA, Antisense ,Transcription factor ,Gene ,030304 developmental biology ,0303 health sciences ,Adenine ,030302 biochemistry & molecular biology ,Adenosine Diphosphate ,[SDV] Life Sciences [q-bio] ,chemistry ,Trans-Activators ,Transcriptome ,Gene Deletion ,DNA - Abstract
International audience; Transposable elements play a fundamental role in genome evolution. It is proposed that their mobility, activated under stress, induces mutations that could confer advantages to the host organism. Transcription of the Ty1 LTR-retrotransposon of Saccharomyces cerevisiae is activated in response to a severe deficiency in adenylic nucleotides. Here, we show that Ty2 and Ty3 are also stimulated under these stress conditions, revealing the simultaneous activation of three active Ty retrotransposon families. We demonstrate that Ty1 activation in response to adenylic nucleotide depletion requires the DNA-binding transcription factor Tye7. Ty1 is transcribed in both sense and antisense directions. We identify three Tye7 potential binding sites in the region of Ty1 DNA sequence where antisense transcription starts. We show that Tye7 binds to Ty1 DNA and regulates Ty1 antisense transcription. Altogether, our data suggest that, in response to adenylic nucleotide reduction, TYE7 is induced and activates Ty1 mRNA transcription, possibly by controlling Ty1 antisense transcription. We also provide the first evidence that Ty1 antisense transcription can be regulated by environmental stress conditions, pointing to a new level of control of Ty1 activity by stress, as Ty1 antisense RNAs play an important role in regulating Ty1 mobility at both the transcriptional and post-transcriptional stages.
- Published
- 2012
28. The yeast BDF1 gene encodes a transcription factor involved in the expression of a broad class of genes including snRNAs
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Zoi Lygerou, Pascale Lesage, Christine Conesa, Anny Ruet, Marian Carlson, André Sentenac, Robert N. Swanson, and Bertrand Séraphin
- Subjects
Saccharomyces cerevisiae Proteins ,Genes, Fungal ,Molecular Sequence Data ,Mutant ,Gene Dosage ,Prp24 ,Saccharomyces cerevisiae ,Biology ,Gene dosage ,Transcription (biology) ,Gene Expression Regulation, Fungal ,RNA, Small Nuclear ,Genes, Regulator ,Genetics ,snRNP ,Amino Acid Sequence ,Cloning, Molecular ,Gene ,Transcription factor ,Conserved Sequence ,Regulation of gene expression ,Base Sequence ,Temperature ,Chromosome Mapping ,Sequence Analysis, DNA ,Mutation ,Chromosomes, Fungal ,Sequence Alignment ,Transcription Factors - Abstract
While screening for genes that affect the synthesis of yeast snRNPs, we identified a thermosensitive mutant that abolishes the production of a reporter snRNA at the non-permissive temperature. This mutant defines a new gene, named BDF1. In a bdf1-1 strain, the reporter snRNA synthesized before the temperature shift remains stable at the non-permissive temperature. This demonstrates that the BDF1 gene affects the synthesis rather than the stability of the reporter snRNA and suggests that the BDF1 gene encodes a transcription factor. BDF1 is present in single copy on yeast chromosome XII, and is important for normal vegetative growth but not essential for cell viability. bdf1 null mutants share common phenotypes with several mutants affecting general transcription and are defective in snRNA production. BDF1 encodes a protein of 687 amino-acids containing two copies of the bromodomain, a motif also present in other transcription factors as well as a new conserved domain, the ET domain, also present in Drosophila and human proteins.
- Published
- 1994
29. Analysis of the SIP3 protein identified in a two-hybrid screen for interaction with the SNF1 protein kinase
- Author
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Xiaolu Yang, Marian Carlson, and Pascale Lesage
- Subjects
Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Genes, Fungal ,Molecular Sequence Data ,Saccharomyces cerevisiae ,Protein Serine-Threonine Kinases ,MAP3K7 ,SYT1 ,Gene Expression Regulation, Enzymologic ,Fungal Proteins ,Gene Expression Regulation, Fungal ,Genetics ,Amino Acid Sequence ,Cloning, Molecular ,Base Sequence ,biology ,MAPKAPK2 ,fungi ,Cyclin-dependent kinase 2 ,Autophagy-related protein 13 ,Molecular biology ,GPS2 ,carbohydrates (lipids) ,GATAD2B ,biology.protein ,Cyclin-dependent kinase 7 ,Plasmids ,Transcription Factors - Abstract
The Saccharomyces cerevisiae SIP3 gene was identified in a two-hybrid screen for proteins that interact in vivo with the SNF1 protein kinase, which is necessary for release of glucose repression. We showed that the C-terminal part of SIP3, recovered through its ability to interact with SNF1, strongly activates transcription when tethered to DNA. We have cloned and sequenced the entire SIP3 gene. The predicted 142-kD SIP3 protein contains a putative leucine zipper motif located in its C terminus. The native SIP3 protein also interacts with DNA-bound SNF1 and activates transcription of a target gene. A complete deletion of the SIP3 gene did not confer phenotypes characteristic of snf1 mutants. However, in a mutant deficient for the SNF1 kinase activity due to loss of the SNF4 stimulatory function, increased dosage of SIP3 partially restored expression of the glucose-repressible SUC2 gene. Overexpression of the C terminus of SIP3 caused defects in growth and SUC2 expression which were remedied by overexpressing SNF1. Taken together, these genetic data suggest that SIP3 is functionally related to the SNF1 protein kinase pathway.
- Published
- 1994
30. Messenger RNA secondary structure and translational coupling in the Escherichia coli operon encoding translation initiation factor IF3 and the ribosomal proteins, L35 and L20
- Author
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M. Milet, Claude Chiaruttini, Mathias Springer, J. Dondon, Pascale Lesage, and M. Graffe
- Subjects
DNA, Bacterial ,Ribosomal Proteins ,Transcription, Genetic ,Operon ,Molecular Sequence Data ,Restriction Mapping ,Prokaryotic Initiation Factor-3 ,Biology ,Ribosome ,Bacterial Proteins ,Cistron ,Peptide Initiation Factors ,Structural Biology ,Ribosomal protein ,Protein biosynthesis ,RNA, Messenger ,Molecular Biology ,Base Sequence ,Escherichia coli Proteins ,Prokaryotic initiation factor-3 ,Gene Expression Regulation, Bacterial ,Ribosomal RNA ,equipment and supplies ,Molecular biology ,Ribosomal binding site ,Protein Biosynthesis ,Nucleic Acid Conformation - Abstract
The Escherichia coli infC-rpmI-rplT operon encodes translation initiation factor IF3 and the ribosomal proteins, L35 and L20, respectively. The expression of the last cistron (rplT) has been shown to be negatively regulated at a post-transcriptional level by its own product, L20, which acts at an internal operator located within infC. The present work shows that L20 directly represses the expression of rpmI, and indirectly that of rplT, via translational coupling with rpmI. Deletions and an inversion of the coding region of rpmI, suggest an mRNA secondary structure forming between sequences within rpmI and the translation initiation site of rplT. To verify the existence of this structure, detailed analyses were performed using chemical and enzymatic probes. Also, mutants that uncoupled rplT expression from that of rpmI, were isolated. The mutations fall at positions that would base-pair in the secondary structure. Our model is that L20 binds to its operator within infC and represses the translation of rpmI. When the rpmI mRNA is not translated, it can base-pair with the ribosomal binding site of rplT, sequestering it, and abolishing rplT expression. If the rpmI mRNA is translated, i.e. covered by ribosomes, the inhibitory structure cannot form leaving the translation initiation site of rplT free for ribosomal binding and for full expression. Although translational coupling in ribosomal protein operons has been suspected to be due to the formation of secondary structures that sequester internal ribosomal binding sites, this is the first time that such a structure has been shown to exist.
- Published
- 1992
31. Remodeling Yeast Gene Transcription by Activating the Ty1 Long Terminal Repeat Retrotransposon under Severe Adenine Deficiency▿
- Author
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Carole Pennetier, Pascale Lesage, and Géraldine Servant
- Subjects
Transposable element ,Saccharomyces cerevisiae Proteins ,Retroelements ,Transcription, Genetic ,Genes, Fungal ,Molecular Sequence Data ,Retrotransposon ,Saccharomyces cerevisiae ,Biology ,Chromatin remodeling ,Histones ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Transcriptional regulation ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Alleles ,Genetics ,Regulation of gene expression ,Adenosine Triphosphatases ,Base Sequence ,Adenine ,Terminal Repeat Sequences ,Nuclear Proteins ,Cell Biology ,Articles ,beta-Galactosidase ,Long terminal repeat ,DNA-Binding Proteins ,Mutation ,Transcription Factors - Abstract
The Ty1 long terminal repeat (LTR) retrotransposon of Saccharomyces cerevisiae is a powerful model to understand the activation of transposable elements by stress and their impact on genome expression. We previously discovered that Ty1 transcription is activated under conditions of severe adenine starvation. The mechanism of activation is independent of the Bas1 transcriptional activator of the de novo AMP biosynthesis pathway and probably involves chromatin remodeling at the Ty1 promoter. Here, we show that the 5' LTR has a weak transcriptional activity and is sufficient for the activation by severe adenine starvation. Furthermore, we demonstrate that Ty1 insertions that bring Ty1 promoter sequences into the vicinity of a reporter gene confer adenine starvation regulation on it. We provide evidence that similar coactivation of genes adjacent to Ty1 sequences occurs naturally in the yeast genome, indicating that Ty1 insertions can mediate transcriptional control of yeast gene expression under conditions of severe adenine starvation. Finally, the transcription pattern of genes adjacent to Ty1 insertions suggests that severe adenine starvation facilitates the initiation of transcription at alternative sites, partly located in the 5' LTR. We propose that Ty1-driven transcription of coding and noncoding sequences could regulate yeast gene expression in response to stress.
- Published
- 2008
32. Impact of ionizing radiation on the life cycle of Saccharomyces cerevisiae Ty1 retrotransposon
- Author
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Marie Dutreix, Géraldine Mercier, Pascale Lesage, Mathias Springer, Christine Sacerdot, and Anne-Laure Todeschini
- Subjects
Saccharomyces cerevisiae Proteins ,Retroelements ,Transcription, Genetic ,DNA damage ,Saccharomyces cerevisiae ,Mutant ,Blotting, Western ,Bioengineering ,Retrotransposon ,Applied Microbiology and Biotechnology ,Biochemistry ,Fungal Proteins ,Western blot ,Transcription (biology) ,Complementary DNA ,Gene Expression Regulation, Fungal ,Genetics ,medicine ,biology ,medicine.diagnostic_test ,RNA ,RNA, Fungal ,biology.organism_classification ,Blotting, Northern ,Molecular biology ,Blotting, Southern ,Gamma Rays ,Biotechnology ,DNA Damage ,Transcription Factors - Abstract
Ty1 elements, LTR-retrotransposons of Saccharomyces cerevisiae, are known to be activated by genetic and environmental stress. Several DNA-damaging agents have been shown to increase both Ty1 transcription and retrotransposition. To explore further the relationship between Ty1 mobility and DNA damage, we have studied the impact of ionizing radiation at different steps of the Ty1 life cycle. We have shown that Ty1 transposition is strongly activated by γ-irradiation and we have analysed its effect on Ty1 transcription, TyA1 protein and Ty1 cDNA levels. The activation of transposition rises with increasing doses of γ-rays and is stronger for Ty1 elements than for the related Ty2 elements. Ty1 RNA levels are markedly elevated upon irradiation; however, no significant increase of TyA1 protein was detected as measured by TYA1–lacZ fusions and by Western blot. A moderate increase in Ty1 cDNA levels was also observed, indicating that ionizing radiation can induce the synthesis of Ty1 cDNA. In diploid cells and ste12 mutants, where both Ty1 transcription and transposition are repressed, γ-irradiation is able to activate Ty1 transposition and increases Ty1 RNA levels. These results suggest the existence of a specific regulatory pathway involved in Ty1 response to the γ-irradiation that would be independent of Ste12 and mating-type factors. Our findings also indicate that ionizing radiation acts on several steps of the Ty1 life cycle. Copyright © 2005 John Wiley & Sons, Ltd.
- Published
- 2005
33. Differential effects of chromatin and Gcn4 on the 50-fold range of expression among individual yeast Ty1 retrotransposons
- Author
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Mathias Springer, Lionel Benard, Pascale Lesage, and Antonin Morillon
- Subjects
Transcriptional Activation ,Saccharomyces cerevisiae Proteins ,Retroelements ,Transcription, Genetic ,Chromosomal Proteins, Non-Histone ,Retrotransposon ,Electrophoretic Mobility Shift Assay ,Saccharomyces cerevisiae ,Biology ,Response Elements ,DNA-binding protein ,Fungal Proteins ,Upstream activating sequence ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Gene Silencing ,RNA, Messenger ,Amino Acids ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,Regulation of gene expression ,Genetics ,Transcriptional Regulation ,Binding Sites ,Models, Genetic ,Promoter ,Cell Biology ,Chromatin ,DNA-Binding Proteins ,Nucleic Acid Conformation ,Protein Kinases ,Transcription Factors - Abstract
Approximately 30 copies of the Ty1 retrotransposon are present in the genome of Saccharomyces cerevisiae. Previous studies gave insights into the global regulation of Ty1 transcription but provided no information on the behavior of individual genomic elements. This work shows that the expression of 31 individual Ty1 elements in S288C varies over a 50-fold range. Their transcription is repressed by chromatin structures, which are antagonized by the Swi/Snf and SAGA chromatin-modifying complexes in highly expressed Ty1 elements. These elements carry five potential Gcn4 binding sites in their promoter regions that are mostly absent in weakly expressed Ty1 copies. Consistent with this observation, Gcn4 activates the transcription of highly expressed Ty1 elements only. One of the potential Gcn4 binding sites acts as an upstream activating sequence in vivo and interacts with Gcn4 in vitro. Since Gcn4 has been shown to interact with Swi/Snf and SAGA, we predict that Gcn4 activates Ty1 transcription by targeting these complexes to specific Ty1 promoters.
- Published
- 2002
34. Activation of the Kss1 invasive-filamentous growth pathway induces Ty1 transcription and retrotransposition in Saccharomyces cerevisiae
- Author
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Mathias Springer, Pascale Lesage, and Antonin Morillon
- Subjects
MAPK/ERK pathway ,Saccharomyces cerevisiae Proteins ,Retroelements ,Transcription, Genetic ,MAP Kinase Signaling System ,Nitrogen ,Saccharomyces cerevisiae ,MAPK cascade ,DNA-binding protein ,Fungal Proteins ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Molecular Biology ,Transcription factor ,Genetics ,Regulation of gene expression ,biology ,Promoter ,Cell Biology ,biology.organism_classification ,Adaptation, Physiological ,Diploidy ,DNA Dynamics and Chromosome Structure ,DNA-Binding Proteins ,Schizosaccharomyces pombe Proteins ,Mitogen-Activated Protein Kinases ,Transcription Factors - Abstract
Using a set of genomic TY1A-lacZ fusions, we show that Ste12 and Tec1, two transcription factors of the Kss1 mitogen-activated protein kinase (MAPK) cascade activate Ty1 transcription in Saccharomyces cerevisiae. This result strongly suggests that the invasive-filamentous pathway regulates Ty1 transcription. Since this pathway is active in diploid cells, we suspected that Ty1 transposition might occur in this cell type, despite the fact that this event has been never reported before (unless activated by heterologous promoters such as that of GAL1). We demonstrate here that constitutive activation of the invasive-filamentous pathway by the STE11-4 allele or by growth in low-nitrogen medium induces Ty1 transcription and retrotransposition in diploid cells. We show that Ty1 retrotransposition can be activated by STE11-4 in haploid cells as well. Our findings provide the first evidence that Ty1 retrotransposition can be activated by environmental signals that affect differentiation. Activation of the Kss1 MAPK cascade by stress is known to cause filament formation that permits the search for nutrients away from the colonization site. We propose that activation of Ty1 retrotransposition by this cascade could play a role in adaptive mutagenesis in response to stress.
- Published
- 2000
35. Yeast SNF1 protein kinase interacts with SIP4, a C6 zinc cluster transcriptional activator: a new role for SNF1 in the glucose response
- Author
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Xiaolu Yang, Pascale Lesage, and Marian Carlson
- Subjects
Snf3 ,Leucine zipper ,Saccharomyces cerevisiae Proteins ,Molecular Sequence Data ,Saccharomyces cerevisiae ,Biology ,Protein Serine-Threonine Kinases ,DNA-binding protein ,Polymerase Chain Reaction ,Fungal Proteins ,Suppression, Genetic ,Gene Expression Regulation, Fungal ,Consensus Sequence ,Amino Acid Sequence ,Cloning, Molecular ,Molecular Biology ,Transcription factor ,DNA Primers ,Regulation of gene expression ,Zinc finger ,Leucine Zippers ,Base Sequence ,Sequence Homology, Amino Acid ,Activator (genetics) ,fungi ,Zinc Fingers ,Cell Biology ,beta-Galactosidase ,carbohydrates (lipids) ,DNA-Binding Proteins ,Basic-Leucine Zipper Transcription Factors ,Glucose ,Biochemistry ,biology.protein ,Trans-Activators ,Catabolite activator protein ,Transcription Factors ,Research Article - Abstract
The SNF1 protein kinase has been widely conserved in plants and mammals. In Saccharomyces cerevisiae, SNF1 is essential for expression of glucose-repressed genes in response to glucose deprivation. Previous studies supported a role for SNF1 in relieving transcriptional repression. Here, we report evidence that SNF1 modulates function of a transcriptional activator, SIP4, which was identified in a two-hybrid screen for interaction with SNF1. The N terminus of the predicted 96-kDa SIP4 protein is homologous to the DNA-binding domain of the GAL4 family of transcriptional activators, with a C6 zinc cluster adjacent to a coiled-coil motif The C terminus contains a leucine zipper motif and an acidic region. When bound to DNA, a LexA-SIP4 fusion activates transcription of a reporter gene. Transcriptional activation by SIP4 is regulated by glucose and depends on the SNF1 protein kinase. Moreover, SIP4 is differentially phosphorylated in response to glucose availability, and phosphorylation requires SNF1. These findings suggest that the SNF1 kinase interacts with a transcriptional activator to modulate its activity and provide the first direct evidence for a role of SNF1 in activating transcription in response to glucose limitation.
- Published
- 1996
36. Domains of the Escherichia coli threonyl-tRNA synthetase translational operator and their relation to threonine tRNA isoacceptors
- Author
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Pascale Romby, J. Dondon, Hervé Moine, Pascale Lesage, Joël Caillet, Mathias Springer, Chantal Ehresmann, Bernard Ehresmann, Marianne Grunberg-Manago, M. Graffe, and Claude Brunel
- Subjects
Recombinant Fusion Proteins ,Molecular Sequence Data ,Wobble base pair ,Biology ,medicine.disease_cause ,Ribosome ,Gene Expression Regulation, Enzymologic ,Structural Biology ,medicine ,Escherichia coli ,Threonine-tRNA Ligase ,RNA, Messenger ,Binding site ,Molecular Biology ,RNA, Transfer, Thr ,Mutation ,Base Sequence ,Translation (biology) ,Gene Expression Regulation, Bacterial ,Ribosomal binding site ,RNA, Bacterial ,Biochemistry ,Protein Biosynthesis ,Transfer RNA ,Mutagenesis, Site-Directed ,Nucleic Acid Conformation ,T arm - Abstract
The expression of the gene for threonyl-tRNA synthetase ( thrS ) is negatively autoregulated at the translational level in Escherichia coli . The synthetase binds to a region of the thrS leader mRNA upstream from the ribosomal binding site inhibiting subsequent translation. The leader mRNA consists of four structural domains. The present work shows that mutations in these four domains affect expression and/or regulation in different ways. Domain 1, the 3′ end of the leader, contains the ribosomal binding site, which appears not to be essential for synthetase binding. Mutations in this domain probably affect regulation by changing the competition between the ribosome and the synthetase for binding to the leader. Domain 2, 3′ from the ribosomal binding site, is a stem and loop with structural similarities to the tRNA Thr anticodon arm. In tRNAs the anticodon loop is seven nucleotides long, mutations that increase or decrease the length of the anticodon-like loop of domain 2 from seven nucleotides abolish control. The nucleotides in the second and third positions of the anticodon-like sequence are essential for recognition and the nucleotide in the wobble position is not, again like tRNA Thr . The effect of mutations in domain 3 indicate that it acts as an articulation between domains 2 and 4. Domain 4 is a stable arm that has similarities to the acceptor arm of tRNA Thr and is shown to be necessary for regulation. Based on this mutational analysis and previous footprinting experiments, it appears that domains 2 and 4, those analogous to tRNA Thr , are involved in binding the synthetase which inhibits translation probably by interfering with ribosome loading at the nearby translation initiation site.
- Published
- 1992
37. Translated translational operator in Escherichia coli. Auto-regulation in the infC-rpmI-rplT operon
- Author
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H.-N. Truong, Mathias Springer, Pascale Lesage, J. Dondon, and M. Graffe
- Subjects
Genetic Markers ,Ribosomal Proteins ,Operator (biology) ,Operator Regions, Genetic ,Operon ,Molecular Sequence Data ,Restriction Mapping ,lac operon ,Prokaryotic Initiation Factor-3 ,Biology ,Start codon ,Cistron ,Bacterial Proteins ,Structural Biology ,Peptide Initiation Factors ,Escherichia coli ,RNA, Messenger ,Promoter Regions, Genetic ,Molecular Biology ,Regulation of gene expression ,Genetics ,Base Sequence ,Gene Expression Regulation, Bacterial ,Open reading frame ,Genes ,Lac Operon ,Regulatory sequence ,Protein Biosynthesis ,Mutation - Abstract
The genes coding for translation initiation factor IF3 (infC) and for the ribosomal proteins L35 (rpmI) and L20 (rplT) are transcribed in that order from a promoter in front of infC. The last two cistrons of the operon (rpmI and rplT) can be transcribed from a weak secondary promoter situated within the first cistron (infC). Previous experiments have shown that the expression of infC, the first cistron of the operon, is negatively autoregulated at the translational level and that the abnormal AUU initiation codon of infC is responsible for the control. We show that the expression of the last cistron (rplT) is also autoregulated at the posttranscriptional level. The L20 concentration regulates the level of rplT expression by acting in trans at a site located within the first cistron (infC) and thus different from that at which IF3 is known to act. This regulatory site, several hundred nucleotides upstream from the target gene (rplT), was identified through deletions, insertions and a point mutation. Thus, the expression of the operon is controlled in trans by the products of two different cistrons acting at two different sites. The localization within an open reading frame (infC) of a regulatory site acting in cis on the translation of a downstream gene (rplT) is new and was unforeseen since ribosomes translating through the regulatory site might be expected to impair either the binding of L20 or the mRNA secondary structure change caused by the binding. The possible competition between translation of the regions acting in cis and the regulation of the expression of the target gene is discussed.
- Published
- 1990
38. The relation between catalytic activity and gene regulation in the case of E coli threonyl-tRNA synthetase
- Author
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J. Dondon, Chantal Ehresmann, Hervé Moine, Pascale Romby, Marianne Grunberg-Manago, Jean-Pierre Ebel, Mathias Springer, Pascale Lesage, Bernard Ehresmann, and M. Graffe
- Subjects
Binding Sites ,Base Sequence ,Molecular Sequence Data ,RNA ,Aminoacylation ,Translation (biology) ,General Medicine ,Gene Expression Regulation, Bacterial ,Biology ,Biochemistry ,Ribosome ,Ribosomal binding site ,RNA, Bacterial ,Protein Biosynthesis ,Transfer RNA ,Translational regulation ,Mutation ,Escherichia coli ,Threonine-tRNA Ligase ,Nucleic Acid Conformation ,RNA, Messenger ,Binding site - Abstract
The expression of the gene for threonyl-tRNA synthetase ( thrS ) has previously been shown as being negatively autoregulated at the translational level. The region of the thrS leader mRNA responsible for that control is located immediately upstream of the ribosomal binding site, and was proposed to fold in a tRNA Thr anticodon arm-like structure. The present paper reviews experiments using enzymatic and chemical probes that prove the existence of a tRNA Thr anticodon-like structure in the thrS mRNA. These structural studies have also shown the presence of another arm upstream in the leader mRNA that has striking similarities with the acceptor arm of the tRNA Thr isoacceptors. This second arm was shown, by mutational analysis, to also be involved in thrS regulation. Footprinting experiments have shown that both the anticodon-like and the acceptor-like arms interact with the synthetase. Finally, the similarity of the interaction of the synthetase with its 2 RNA ligands (mRNA and tRNA) has been investigated by selecting and studying mutants of the synthetase itself. The observed correlation between regulatory and aminoacylation defects in these mutants strongly suggests that the synthetase recognizes similar regions of its 2 RNA ligands in an analogous manner.
- Published
- 1990
39. Translational Feedback Control in E.Coli: The Role of tRNAThr and tRNAThr-Like Structures in the Operator of the Gene for Threonyl-tRNA Synthetase
- Author
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M. Springer, Hervé Moine, M. Graffe, J.-P. Ebel, Pascale Lesage, J. Dondon, P. Romby, C. Ehresmann, M. Grunberg-Manago, and B. Ehresmann
- Subjects
Genetics ,Ribosomal protein ,Chemistry ,Transfer RNA ,Translation (biology) ,Binding site ,Ribosomal RNA ,Gene ,Ribosome ,Ribosomal binding site ,Cell biology - Abstract
In prokaryotes, protein-mediated translational control often takes the form of a negative feedback (Gold, 1988; Lindahl et al., 1986). The translational repressor, as proven in some examples, interacts with a regulatory region of its own mRNA, affecting ribosome binding and thus translation. In some cases in bacteriophage and E.coli, a particular feedback was shown to belong to a more general regulatory system. For instance, a particular feedback due to a specific ribosomal regulatory protein is modulated by the cellular concentration of the ribosomal RNA (rRNA) to which it binds (Nomura et al., 1984). If the cellular rRNA concentration increases, the specific regulatory protein binds to the excess of rRNA and not to its own mRNA whose translation is increased. This mRNA-rRNA competition permits the ribosomal protein synthesis to be adapted to the cellular rRNA concentration. As suggested in several cases, the binding site of the ribosomal regulatory protein on both its ligands (mRNA and rRNA) could share some similarity. This hypothesis has been called molecular mimicry (Campbell et al, 1983) and implies that there is a common site on the regulatory protein that recognises both nucleic acid ligands. This is a simple strategy for adding a regulatory role to a protein involved in nucleic acid binding without having the necessity for a separate regulatory domain.
- Published
- 1990
40. Condensin-Mediated Chromosome Folding and Internal Telomeres Drive Dicentric Severing by Cytokinesis
- Author
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Natalja Barinova, Romain Koszul, Stéphane Marcand, Alice Deshayes, Claire Béneut, Karine Dubrana, Virginia Lopez, Agnès Thierry, Thomas Guerin, Luciana Lazar-Stefanita, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by funding to S.M. from Fondation ARC, EDF, CEA Radiobiology call, DRF-Impulsion (4D-DSB-DIC), and ANR (DICENs-ANR-14-CE10-0021-01), to K.D. from the European Research Council under the Seventh Framework Program (FP7/2007 2013/ERC grant agreement 281287), and to R.K. from the European Research Council under the Horizon 2020 Program (ERC grant agreement 260822). T.M.G. was supported by a PhD fellowship from CEA, ANR, and a Fondation ARC young researcher grant., We thank Angela Taddei for lacI, lacI∗∗, and lacO array plasmids and suggestions, Frank Uhlmann and Thomas Kuilman for the G20 plasmid, Helle Ulrich for the AID tool kit, Didier Busso and Eléa Dizet (CIGEX platform) for the Rap1 sites plasmids, Pascale Lesage for the anti-Dps1 antibody, Rémi Montagne for assistance with the Hi-C data, Romain Le Bars (IMAGE-GIF platform) and Lamya Irbah (IRCM microscopy platform) for assistance with higher-resolution microscopy, Dan Throsby for text editing, and John Marko, Damien D’Amours, Sarah Lambert, François-Xavier Barre, Pablo Radicella, Eric Coïc, Laurent Maloisel, Paul-Henri Roméo, Mathias Toulouze, and Maoussi Lhuillier-Akakpo for fruitful discussions and suggestions., ANR-14-CE10-0021,DICENs,Prévention et résolution des chromosomes dicentriques(2014), European Project: 281287,EC:FP7:ERC,ERC-2011-StG_20101109,NDOGS(2012), European Project: 260822,EC:FP7:ERC,ERC-2010-StG_20091118,DICIG(2011), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Condensin ,Gene Expression ,yeast ,Shelterin Complex ,MESH: Telomere-Binding Proteins ,chemistry.chemical_compound ,Chromosome Breakpoints ,0302 clinical medicine ,MESH: Saccharomyces cerevisiae Proteins ,Hi-C ,MESH: Models, Genetic ,DNA, Fungal ,Adenosine Triphosphatases ,0303 health sciences ,biology ,SMC ,MESH: Karyotype ,MESH: Chromosome Breakpoints ,MESH: Transcription Factors ,Telomere ,MESH: Saccharomyces cerevisiae ,MESH: Chromosomes, Fungal ,Cell biology ,DNA-Binding Proteins ,Chromosomes, Fungal ,mutagenesis ,lacI ,MESH: Cytokinesis ,Saccharomyces cerevisiae Proteins ,MESH: Gene Expression ,Saccharomyces cerevisiae ,Karyotype ,Telomere-Binding Proteins ,03 medical and health sciences ,Dicentric chromosome ,MESH: Adenosine Triphosphatases ,Telophase ,Molecular Biology ,Mitosis ,030304 developmental biology ,Cytokinesis ,mitosis ,Models, Genetic ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Cell Biology ,MESH: Multiprotein Complexes ,biology.organism_classification ,telophase ,abscission ,MESH: DNA, Fungal ,enzymes and coenzymes (carbohydrates) ,chemistry ,Multiprotein Complexes ,biology.protein ,MESH: Telomere ,030217 neurology & neurosurgery ,DNA ,MESH: DNA-Binding Proteins ,Transcription Factors ,condensing - Abstract
International audience; In Saccharomyces cerevisiae, dicentric chromosomes stemming from telomere fusions preferentially break at the fusion. This process restores a normal karyotype and protects chromosomes from the detrimental consequences of accidental fusions. Here, we address the molecular basis of this rescue pathway. We observe that tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. We also show that condensins generate forces sufficient to rapidly refold dicentrics prior to breakage by cytokinesis and are essential to the preferential breakage at telomere fusions. Thus, the rescue of fused telomeres results from a condensin- and Rap1-driven chromosome folding that favors fusion entrapment where abscission takes place. Because a close spacing between the DNA-bound Rap1 molecules is essential to this process, Rap1 may act by stalling condensins.
- Published
- 2019
41. Potent neutralizing antibodies in humans infected with zoonotic simian foamy viruses target conserved epitopes located in the dimorphic domain of the surface envelope protein
- Author
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Augustin Mouinga-Ondémé, Dirk Lindemann, Joelle Tobaly-Tapiero, Richard Njouom, Antoine Gessain, Caroline Lambert, Réjane Rua, Florence Buseyne, Julie Gouzil, Léa Richard, Edouard Betsem, Mathilde Couteaudier, Thomas Montange, Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institute of Virology [Dresden], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Centre International de Recherches Médicales de Franceville (CIRMF), CL was personally supported by a doctoral grant from the French government program Investissement d'Avenir, Laboratory of Excellence, Integrative Biology of Emerging Infectious Diseases (LabEx IBEID, http://www.agence-nationale-recherche.fr/ProjetIA-10-LABX-0062). LR was personally supported by the Bourse de l’Ecole Normale Supérieure, Faculté Paris Diderot, http://www.ens.fr/. This work was supported by the Institut Pasteur in Paris, France, the Programme Transversal de Recherche from the Institut Pasteur [PTR#437], https://www.pasteur.fr/fr, and the Agence Nationale de la Recherche [grant ANR-10-LABX-62-IBEID, REEMFOAMY project, ANR 15-CE-15-0008-01, We thank P. Souque, C. Blanc, and P. Afonso for their helpful advice on the molecular biology experiments. We are indebted to Pascale Lesage, Alessia Zamborlini, Ali Saïb, and Olivier Schwartz for helpful discussions. We thank members from the EPVO research unit for discussions and technical advices., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-15-CE15-0008,REEMFOAMY,L'infection humaine par les virus foamy simiens zoonotiques : rôle des facteurs virologiques et immunologiques dans la restrcition de l'emergence virale(2015), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Dresden (TUD), Centre international de recherches médicales de Franceville (CIRMF), Organisation Mondiale de la Santé (OMS), and ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010)
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Male ,0301 basic medicine ,Physiology ,viruses ,Artificial Gene Amplification and Extension ,Disease Vectors ,Blood plasma ,Simian ,Biochemistry ,Epitope ,Neutralization ,Epitopes ,Viral Envelope Proteins ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Immune Physiology ,Zoonoses ,Medicine and Health Sciences ,Viral replication ,lcsh:QH301-705.5 ,Mammals ,[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,education.field_of_study ,Immune System Proteins ,Eukaryota ,virus diseases ,Hominidae ,Middle Aged ,Body Fluids ,Polymerase chain reaction ,3. Good health ,Blood ,Infectious Diseases ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,Vertebrates ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Apes ,Anatomy ,Antibody ,Research Article ,Primates ,Adult ,lcsh:Immunologic diseases. Allergy ,Gorillas ,Pan troglodytes ,Immunology ,Population ,Biology ,Research and Analysis Methods ,Microbiology ,Antibodies ,Viral vector ,03 medical and health sciences ,Simian foamy virus ,Virology ,Genetics ,Animals ,Humans ,Amino Acid Sequence ,Chimpanzees ,Molecular Biology Techniques ,education ,Molecular Biology ,Gene ,[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics ,Binding Sites ,Gorilla gorilla ,Co-infections ,Organisms ,Biology and Life Sciences ,Proteins ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Antibodies, Neutralizing ,030104 developmental biology ,lcsh:Biology (General) ,Amniotes ,biology.protein ,Parasitology ,lcsh:RC581-607 ,Retroviridae Infections - Abstract
Human diseases of zoonotic origin are a major public health problem. Simian foamy viruses (SFVs) are complex retroviruses which are currently spilling over to humans. Replication-competent SFVs persist over the lifetime of their human hosts, without spreading to secondary hosts, suggesting the presence of efficient immune control. Accordingly, we aimed to perform an in-depth characterization of neutralizing antibodies raised by humans infected with a zoonotic SFV. We quantified the neutralizing capacity of plasma samples from 58 SFV-infected hunters against primary zoonotic gorilla and chimpanzee SFV strains, and laboratory-adapted chimpanzee SFV. The genotype of the strain infecting each hunter was identified by direct sequencing of the env gene amplified from the buffy coat with genotype-specific primers. Foamy virus vector particles (FVV) enveloped by wild-type and chimeric gorilla SFV were used to map the envelope region targeted by antibodies. Here, we showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Neutralizing antibodies target the dimorphic portion of the envelope protein surface domain. Epitopes recognized by neutralizing antibodies have been conserved during the cospeciation of SFV with their nonhuman primate host. Greater neutralization breadth in plasma samples of SFV-infected humans was statistically associated with smaller SFV-related hematological changes. The neutralization patterns provide evidence for persistent expression of viral proteins and a high prevalence of coinfection. In conclusion, neutralizing antibodies raised against zoonotic SFV target immunodominant and conserved epitopes located in the receptor binding domain. These properties support their potential role in restricting the spread of SFV in the human population., Author summary Foamy viruses are the oldest known retroviruses and have been mostly described to be nonpathogenic in their natural animal hosts. Simian foamy viruses (SFVs) can be transmitted to humans, in whom they establish persistent infection, as have the simian lenti- and deltaviruses that led to the emergence of two major human pathogens, human immunodeficiency virus type 1 (HIV-1) and human T lymphotropic virus type 1 (HTLV-1). Such cross-species transmission of SFV is ongoing in many parts of the world where humans have contact with nonhuman primates. We present the first comprehensive study of neutralizing antibodies in SFV-infected humans. We showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Neutralizing antibodies target the dimorphic portion of the envelope protein surface domain that overlap with the receptor binding domain. SFV-specific antibodies target epitopes conserved over 8 million years of co-speciation with their nonhuman primate host. Greater neutralization potency in infected individuals was statistically associated with smaller SFV-related hematological changes. In conclusion, our results suggest the protective action of neutralizing antibodies against SFV infection and spread in the human population.
- Published
- 2018
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