Search

Your search keyword '"Liudmyla Lototska"' showing total 9 results
Start Over Author "Liudmyla Lototska"
9 results on '"Liudmyla Lototska"'

1. ZNF524 directly interacts with telomeric DNA and supports telomere integrity

Author

Hanna Braun, Ziyan Xu, Fiona Chang, Nikenza Viceconte, Grishma Rane, Michal Levin, Liudmyla Lototska, Franziska Roth, Alexia Hillairet, Albert Fradera-Sola, Vartika Khanchandani, Zi Wayne Sin, Wai Khang Yong, Oliver Dreesen, Yang Yang, Yunyu Shi, Fudong Li, Falk Butter, and Dennis Kappei

Subjects
Science
Abstract

Abstract Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing nonhomologous end joining (NHEJ) through its subunit TRF2. Here, we describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity, and reveal base-specific sequence recognition by cocrystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.

Published
2023
Full Text
View/download PDF

2. The Telomeric Protein TRF2 Regulates Replication Origin Activity within Pericentromeric Heterochromatin

Author

Serge Bauwens, Liudmyla Lototska, Stephane Koundrioukoff, Michelle Debatisse, Jing Ye, Eric Gilson, and Aaron Mendez-Bermudez

Subjects
TRF2, heterochromatin, pericentromeric DNA, ORC, replication, telomeres, Science
Abstract

Heterochromatic regions render the replication process particularly difficult due to the high level of chromatin compaction and the presence of repeated DNA sequences. In humans, replication through pericentromeric heterochromatin requires the binding of a complex formed by the telomeric factor TRF2 and the helicase RTEL1 in order to relieve topological barriers blocking fork progression. Since TRF2 is known to bind the Origin Replication Complex (ORC), we hypothesized that this factor could also play a role at the replication origins (ORI) of these heterochromatin regions. By performing DNA combing analysis, we found that the ORI density is higher within pericentromeric satellite DNA repeats than within bulk genomic DNA and decreased upon TRF2 downregulation. Moreover, we showed that TRF2 and ORC2 interact in pericentromeric DNA, providing a mechanism by which TRF2 is involved in ORI activity. Altogether, our findings reveal an essential role for TRF2 in pericentromeric heterochromatin replication by regulating both replication initiation and elongation.

Published
2021
Full Text
View/download PDF

3. ZNF524 directly interacts with telomeric DNA and supports telomere integrity

Author

Hanna Braun, Ziyan Xu, Fiona Chang, Nikenza Viceconte, Grishma Rane, Michal Levin, Liudmyla Lototska, Franziska Roth, Alexia Hillairet, Albert Fradera-Sola, Vartika Khanchandani, Oliver Dreesen, Yang Yang, Yunyu Shi, Fudong Li, Falk Butter, and Dennis Kappei

Abstract

Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. We here describe ZNF524, a zinc finger protein that directly binds telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, ZNF524 is a direct telomere-binding protein involved in the maintenance of telomere integrity.

Published
2022
Full Text
View/download PDF

4. Selective pericentromeric heterochromatin dismantling caused by TP53 activation during senescence

Author

Sarantis Gagos, Olivier Croce, Florent Tessier, Yiming Lu, Joe Nassour, Liudmyla Lototska, Xiaohua Jiang, Eric Gilson, Jing Ye, Mélanie Pousse, Chrysa M Latrick, Corinne Abbadie, Aaron Mendez-Bermudez, and Veronica Cherdyntseva

Subjects
Senescence, Centromere, Down-Regulation, Telomere, Biology, Chromatin, Cell Line, Cell biology, Heterochromatin, Genetics, Humans, Telomeric Repeat Binding Protein 2, Tumor Suppressor Protein p53, Cellular Senescence, Telomere Shortening, DNA Damage, HeLa Cells, Pericentromeric heterochromatin
Abstract

Cellular senescence triggers various types of heterochromatin remodeling that contribute to aging. However, the age-related mechanisms that lead to these epigenetic alterations remain elusive. Here, we asked how two key aging hallmarks, telomere shortening and constitutive heterochromatin loss, are mechanistically connected during senescence. We show that, at the onset of senescence, pericentromeric heterochromatin is specifically dismantled consisting of chromatin decondensation, accumulation of DNA breakages, illegitimate recombination and loss of DNA. This process is caused by telomere shortening or genotoxic stress by a sequence of events starting from TP53-dependent downregulation of the telomere protective protein TRF2. The resulting loss of TRF2 at pericentromeres triggers DNA breaks activating ATM, which in turn leads to heterochromatin decondensation by releasing KAP1 and Lamin B1, recombination and satellite DNA excision found in the cytosol associated with cGAS. This TP53–TRF2 axis activates the interferon response and the formation of chromosome rearrangements when the cells escape the senescent growth arrest. Overall, these results reveal the role of TP53 as pericentromeric disassembler and define the basic principles of how a TP53-dependent senescence inducer hierarchically leads to selective pericentromeric dismantling through the downregulation of TRF2.

Published
2021
Full Text
View/download PDF

5. The Telomeric Protein TRF2 Regulates Replication Origin Activity within Pericentromeric Heterochromatin

Author

Jing Ye, Serge Bauwens, Liudmyla Lototska, Stephane Koundrioukoff, Michelle Debatisse, Aaron Mendez-Bermudez, Eric Gilson, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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), Institut Gustave Roussy (IGR), Intégrité du génome et cancers (IGC), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and Shanghai Jiao Tong University [Shanghai]

Subjects
replication, Heterochromatin, Satellite DNA, pericentromeric DNA, TRF2, Origin of replication, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:Science, ORC2, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, biology, heterochromatin, Paleontology, Helicase, telomeres, Chromatin, Cell biology, chemistry, ORC, Space and Planetary Science, Replication Initiation, biology.protein, lcsh:Q, 030217 neurology & neurosurgery, DNA
Abstract

International audience; Heterochromatic regions render the replication process particularly difficult due to the high level of chromatin compaction and the presence of repeated DNA sequences. In humans, replication through pericentromeric heterochromatin requires the binding of a complex formed by the telomeric factor TRF2 and the helicase RTEL1 in order to relieve topological barriers blocking fork progression. Since TRF2 is known to bind the Origin Replication Complex (ORC), we hypothesized that this factor could also play a role at the replication origins (ORI) of these heterochromatin regions. By performing DNA combing analysis, we found that the ORI density is higher within pericentromeric satellite DNA repeats than within bulk genomic DNA and decreased upon TRF2 downregulation. Moreover, we showed that TRF2 and ORC2 interact in pericentromeric DNA, providing a mechanism by which TRF2 is involved in ORI activity. Altogether, our findings reveal an essential role for TRF2 in pericentromeric heterochromatin replication by regulating both replication initiation and elongation.

Published
2021
Full Text
View/download PDF

6. Human RAP 1 specifically protects telomeres of senescent cells from DNA damage

Author

Marie-Josèphe Giraud-Panis, Jia-Xing Yue, Liudmyla Lototska, Nicola J. Royle, Jing Li, Jing Ye, Zhou Songyang, Aaron Mendez-Bermudez, Gianni Liti, Eric Gilson, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)

Subjects
DNA Replication, Telomerase, endocrine system, DNA damage, telomeres Subject Categories Autophagy & Cell Death, Telomere Capping, [SDV]Life Sciences [q-bio], Telomere-Binding Proteins, Biology, Biochemistry, non-homologous end joining, 03 medical and health sciences, replicative senescence, 0302 clinical medicine, Report, Genetics, chromosome fusions, Animals, Humans, Molecular Biology, Cellular Senescence, Recombination & Repair, 030304 developmental biology, 0303 health sciences, RAP1, DNA replication, DNA Replication, Repair & Recombination, Telomere, telomeres, Cell biology, Non-homologous end joining, Transcription Factor AP-1, enzymes and coenzymes (carbohydrates), non‐homologous end joining, Rap1, Autophagy & Cell Death, Homologous recombination, 030217 neurology & neurosurgery, DNA Damage, HeLa Cells, Reports
Abstract

Repressor/activator protein 1 (RAP1) is a highly evolutionarily conserved protein found at telomeres. Although yeast Rap1 is a key telomere capping protein preventing non‐homologous end joining (NHEJ) and consequently telomere fusions, its role at mammalian telomeres in vivo is still controversial. Here, we demonstrate that RAP1 is required to protect telomeres in replicative senescent human cells. Downregulation of RAP1 in these cells, but not in young or dividing pre‐senescent cells, leads to telomere uncapping and fusions. The anti‐fusion effect of RAP1 was further explored in a HeLa cell line where RAP1 expression was depleted through an inducible CRISPR/Cas9 strategy. Depletion of RAP1 in these cells gives rise to telomere fusions only when telomerase is inhibited. We further show that the fusions triggered by RAP1 loss are dependent upon DNA ligase IV. We conclude that human RAP1 is specifically involved in protecting critically short telomeres. This has important implications for the functions of telomeres in senescent cells., Human RAP1 specifically protects critically short telomeres from DNA damage response activation and telomere fusions in replicative senescent fibroblasts and tumor cells upon telomerase inhibition.

Published
2020
Full Text
View/download PDF

7. Mitochondrial function in skeletal myofibers is controlled by a TRF2‐SIRT3 axis over lifetime

Author

Sabrina Sacconi, Liudmyla Lototska, Laurent Schaeffer, Jérôme D. Robin, Camille Laberthonnière, Mélanie Pousse, Eric Gilson, Jean Luc Thomas, Waiian Leong, Jing Ye, Frédérique Magdinier, Serge Bauwens, Valérie M. Renault, Florent Tessier, Olivier Croce, Han Peng, Maria‐Sol Jacome Burbano, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Male, 0301 basic medicine, Aging, Muscle Fibers, Skeletal, Mitochondrion, Mice, 0302 clinical medicine, Sirtuin 3, Telomeric Repeat Binding Protein 2, Cells, Cultured, Telomere Shortening, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Myogenesis, Middle Aged, Telomere, Mitochondria, Cell biology, medicine.anatomical_structure, Gene Knockdown Techniques, Sirtuin, Female, Original Article, Signal Transduction, Adult, Senescence, Adolescent, SIRT3, Down-Regulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Young Adult, 03 medical and health sciences, Downregulation and upregulation, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, skeletal muscle, Aged, Skeletal muscle, Original Articles, Cell Biology, postmitotic cells, telomeres, 030104 developmental biology, biology.protein, Reactive Oxygen Species, 030217 neurology & neurosurgery
Abstract

Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere‐capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2‐compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2‐compromised human myotubes. Altogether, these results reveal a TRF2‐SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism., The level of the TRF2 protein, a key telomere‐capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes and in mouse skeletal muscle, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Altogether, our results reveal a TRF2‐SIRT3 axis controling muscle mitochondrial function.

Published
2020
Full Text
View/download PDF

8. Genome-wide Control of Heterochromatin Replication by the Telomere Capping Protein TRF2

Author

Michael Schertzer, Arturo Londoño-Vallejo, Aaron Mendez-Bermudez, Michelle Debatisse, Mylène Perderiset, Karine Jamet, Geneviève Almouzni, Jing Ye, Nicolas Nottet, Eric Gilson, Stephane Koundrioukoff, Marie Josèphe Giraud-Panis, Macarena Mowinckel, Liudmyla Lototska, Agurtzane Irizar, Olivier Croce, Serge Bauwens, Mare Paule Teulade-Fichou, International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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), Laboratoire de biologie moléculaire et cellulaire, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Institut Sophia Agrobiotech (ISA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA), Dynamique nucléaire et plasticité du génome (DNPG), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Telomeres and Cancer Laboratory (Lab ellis e Ligue), Telomeres and Cancer Laboratory, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), 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), Institut Sophia Agrobiotech [Sophia Antipolis] (ISA), Institut National de la Recherche Agronomique (INRA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Dynamique du noyau, Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Mechanical Engineering, Sungkyunkwan University [Suwon] (SKKU), 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), Institut Curie, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Université Nice Sophia Antipolis (1965 - 2019) (UNS), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-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)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, biology, Heterochromatin, Telomere Capping, [SDV]Life Sciences [q-bio], Helicase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Chromosome Fragility, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Shelterin, 3. Good health, Chromatin, Cell biology, Telomere, 03 medical and health sciences, 030104 developmental biology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Centromere, biology.protein, Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

Summary Hard-to-replicate regions of chromosomes (e.g., pericentromeres, centromeres, and telomeres) impede replication fork progression, eventually leading, in the event of replication stress, to chromosome fragility, aging, and cancer. Our knowledge of the mechanisms controlling the stability of these regions is essentially limited to telomeres, where fragility is counteracted by the shelterin proteins. Here we show that the shelterin subunit TRF2 ensures progression of the replication fork through pericentromeric heterochromatin, but not centromeric chromatin. In a process involving its N-terminal basic domain, TRF2 binds to pericentromeric Satellite III sequences during S phase, allowing the recruitment of the G-quadruplex-resolving helicase RTEL1 to facilitate fork progression. We also show that TRF2 is required for the stability of other heterochromatic regions localized throughout the genome, paving the way for future research on heterochromatic replication and its relationship with aging and cancer.

Published
2018
Full Text
View/download PDF

9. TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection

Author

Marie-Hélène Le Du, Simona Miron, Bei Pei, Hong Wang, Eric Gilson, Parminder Kaur, Arturo Londoño-Vallejo, Jing Ye, Emilie Jaune, Aaron Mendez-Bermudez, Sabrina Pisano, Marie-Josèphe Giraud-Panis, Vincent Fraisier, Julien Cherfils-Vicini, Nadir Djerbi, Eric Aeby, Delphine Benarroch-Popivker, Serge Bauwens, Kevin Foucher, Chrysa M Latrick, Liudmyla Lototska, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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), 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), International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine, Physics Department, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Swiss Institute for Experimental Cancer Research - Lausanne (ISREC), Swiss Institute for Experimental Cancer Research, Enveloppe Nucléaire, Télomères et Réparation de l’ADN (INTGEN), Département Biochimie, Biophysique et Biologie Structurale (B3S), 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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), ANR-10-BLAN-1512,TELOLOOP,Rôle de la protéine TRF2 et de ses partenaires dans la formation et la stabilité de la t-loop des télomères humains(2010), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), 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 ), North Carolina State University [Raleigh] ( NCSU ), Compartimentation et dynamique cellulaires ( CDC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Swiss Institute for Experimental Cancer Research - Lausanne ( ISREC ), Enveloppe Nucléaire, Télomères et Réparation de l’ADN ( INTGEN ), Département Biochimie, Biophysique et Biologie Structurale ( B3S ), Institut de Biologie Intégrative de la Cellule ( I2BC ), 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 ) -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 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), 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 ) -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 ), 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 ), Dynamique de l'information génétique : bases fondamentales et cancer ( DIG CANCER ), CHU Nice, ANR-1582-30020690,TELOLOOP,ANR-1582-30020690, ANR : LABEX SIGNALIFE,ANR-11-LABX-0028-01, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), 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 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), 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)-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)-Institut de Biologie Intégrative de la Cellule (I2BC), 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)-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), Telomeres and Cancer Laboratory, Institut Curie [Paris], School of Mechanical Engineering, Sungkyunkwan University [Suwon] (SKKU), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Models, Molecular, 0301 basic medicine, DNA End-Joining Repair, [SDV]Life Sciences [q-bio], Ataxia Telangiectasia Mutated Proteins, TRF2, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, Shelterin Complex, chemistry.chemical_compound, Telomeric Repeat Binding Protein 2, Base Pairing, ComputingMilieux_MISCELLANEOUS, Telomere-binding protein, Mutation, telomere, RAP1, DNA topology, DNA wrapping, Signal Transduction, DNA damage, Base pair, Telomere-Binding Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Topology, Article, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, [ SDV ] Life Sciences [q-bio], Lysine, DNA, Cell Biology, Shelterin, Molecular biology, Protein Structure, Tertiary, Telomere, enzymes and coenzymes (carbohydrates), 030104 developmental biology, chemistry, Nucleic Acid Conformation, DNA Damage, HeLa Cells
Abstract

International audience; The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ∼ 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired.

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results