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6 results on '"MESH: X-linked Nuclear Protein"'

1. Regulation of ALT-associated homology-directed repair by polyADP-ribosylation

Author

Ian D. Waddell, Robert W. Sobol, Kate M. Smith, Justin L. Roncaioli, Felipe da Veiga Leprevost, Song My Hoang, Dattatreya Mellacharevu, Dominique Ray-Gallet, Michelle L. Lynskey, Roderick J. O’Sullivan, Ragini Bhargava, Jonathan Barroso-González, Nicole Kaminski, Geneviève Almouzni, Anne R. Wondisford, Jianfeng Li, Donald J. Ogilvie, Alexey I. Nesvizhskii, Dominic I. James, Callen T. Wallace, Simon C. Watkins, Laura García-Expósito, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Manchester [Manchester], University of Michigan [Ann Arbor], University of Michigan System, University of South Alabama, Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-SU, Gestionnaire

Subjects
MESH: Signal Transduction, Poly Adenosine Diphosphate Ribose, Cell Cycle Proteins, Histones, Poly ADP Ribosylation, 0302 clinical medicine, Structural Biology, MESH: RNA, Small Interfering, RNA, Small Interfering, MESH: Histones, 0303 health sciences, PARG, MESH: X-linked Nuclear Protein, biology, MESH: Histone Chaperones, DNA, Neoplasm, MESH: Transcription Factors, MESH: Gene Expression Regulation, Neoplastic, Telomere, Chromatin, Cell biology, Gene Expression Regulation, Neoplastic, MESH: Recombinational DNA Repair, Histone, MESH: Poly Adenosine Diphosphate Ribose, MESH: Epithelial Cells, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Poly(ADP-ribose) Polymerases, Signal Transduction, G2 Phase, X-linked Nuclear Protein, MESH: Cell Line, Tumor, Glycoside Hydrolases, DNA repair, DNA damage, MESH: DNA, Neoplasm, Article, MESH: Chromatin, MESH: Telomere Homeostasis, Homology directed repair, 03 medical and health sciences, MESH: Cell Cycle Proteins, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Glycoside Hydrolases, Humans, Histone Chaperones, Molecular Biology, ATRX, 030304 developmental biology, MESH: DNA Damage, MESH: Humans, MESH: Poly ADP Ribosylation, MESH: Poly(ADP-ribose) Polymerases, Recombinational DNA Repair, Telomere Homeostasis, Epithelial Cells, MESH: G2 Phase, MESH: Protein Processing, Post-Translational, MESH: HeLa Cells, biology.protein, MESH: Telomere, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, DNA Damage, HeLa Cells, Transcription Factors
Abstract

International audience; The synthesis of poly(ADP-ribose) (PAR) reconfigures the local chromatin environment and recruits DNA-repair complexes to damaged chromatin. PAR degradation by poly(ADP-ribose) glycohydrolase (PARG) is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative lengthening of telomeres (ALT). Proteomic analyses uncover a new role for poly(ADP-ribosyl)ation (PARylation) in regulating the chromatin-assembly factor HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during the G2 phase and is required for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells that is mitigated by re-expression of ATRX, a protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response to ATRX deficiency that pervades ALT cancers.

Published
2020
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2. The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas

Author

Pierre Verrelle, Nathalie Grandin, Bruno Pereira, Ahmed Idbaih, Delphine Poncet, François Ducray, Franck Bielle, Pauline Billard, Patrick Lomonte, Jean-Yves Delattre, Dominique Figarella-Branger, Marc Sanson, Caroline Dehais, Catherine Carpentier, Camille Cohen, Michel Charbonneau, Génétique, Reproduction et Développement (GReD), 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), CHU Clermont-Ferrand, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Université de Caen Normandie (UNICAEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Cancer Resistance Exploring and Targeting (CREaT), Université d'Auvergne - Clermont-Ferrand I (UdA), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Pola Network, Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Charles Foix [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 Pierre et Marie Curie - Paris 6 (UPMC), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), and LOMONTE, PATRICK

Subjects
Male, Telomerase, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:RC346-429, MESH: Isocitrate Dehydrogenase, Cohort Studies, 0302 clinical medicine, ATRX loss of expression, Medicine, MESH: Cohort Studies, ComputingMilieux_MISCELLANEOUS, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: X-linked Nuclear Protein, Brain Neoplasms, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, Isocitrate Dehydrogenase, 3. Good health, Gene Expression Regulation, Neoplastic, Secondary glioblastoma, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Anaplastic astrocytoma, Adult, X-linked Nuclear Protein, IDH1, MESH: Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuropathology, Astrocytoma, Pathology and Forensic Medicine, MESH: Telomere Homeostasis, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Alternative lengthening of telomeres, Humans, lcsh:Neurology. Diseases of the nervous system, ATRX, Aged, 030304 developmental biology, IDH1/2 mutations, MESH: Humans, business.industry, Research, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Telomere Homeostasis, Cancer, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, Telomere, MESH: Astrocytoma, Mutation, Cancer cell, Cancer research, Neurology (clinical), business, MESH: Female
Abstract

All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, anda fortioriits quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p

Published
2019
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3. Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

Author

Harikleia Episkopou, Corinne Augé-Gouillou, Marie-Véronique Demattei, Nathalie Grandin, Michel Charbonneau, Rita Eid, Anabelle Decottignies, Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Genetic and Epigenetic Alterations of Genomes (GEAG), Université Catholique de Louvain (UCL)-de Duve Institute, Université Francois Rabelais [Tours], 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), Université catholique de Louvain, Institut des Sciences de la Vie, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), UCL - SSS/DDUV - Institut de Duve, Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain = Catholic University of Louvain (UCL), Université Catholique de Louvain = Catholic University of Louvain (UCL)-de Duve Institute, Université de Tours (UT), Génétique, Reproduction et Développement (GReD), 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), Fondation de France, LIGUE contre le Cancer Grand-Ouest, Université de Tours, and 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)

Subjects
RNA, Untranslated, Transcription, Genetic, Chromosomal Proteins, Non-Histone, [SDV]Life Sciences [q-bio], MESH: DNA Helicases, RNA polymerase II, Cell Cycle Proteins, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: Glioma, MESH: RNA, Untranslated, Transcription (biology), Alternative Lengthening of Telomeres, telomere length, Telomerase, MESH: X-linked Nuclear Protein, MESH: Telomerase, Nuclear Proteins, Glioma, Articles, Telomere, Subtelomere, Chromatin, ATRX, RNA Interference, RNA Polymerase II, X-linked Nuclear Protein, MESH: Cell Line, Tumor, MESH: RNA Interference, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Telomere Homeostasis, MESH: Chromatin, Telomere Homeostasis, MESH: Cell Cycle Proteins, MESH: Chromosomal Proteins, Non-Histone, Cell Line, Tumor, Humans, Molecular Biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Cohesin, MESH: Transcription, Genetic, DNA Helicases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Molecular biology, MESH: RNA Polymerase II, gliomas, biology.protein, MESH: Telomere, Chromatin immunoprecipitation, MESH: Nuclear Proteins
Abstract

International audience; Replication Protein A (RPA) is an evolutionary conserved essential complex with single-stranded DNA binding properties that has been implicated in numerous DNA transactions. At damaged telomeres, Saccharomyces cerevisiae RPA recruits the Mec1-Ddc2 module of the DNA damage checkpoint network, its only known function in DNA damage signaling. Here, we describe rfa1 mutants (rfa1-1, rfa1-9, rfa1-10, rfa1-11 and rfa1-12) that are proficient in this checkpoint but nevertheless exhibit deregulation of cell cycle control upon telomere uncapping induced by the cdc13-1 mutation. Overriding of this damage-induced checkpoint-independent cell cycle block in the rfa1 mutants was suppressed following genetic inactivation of either TEL1 or EST2/telomerase. Altogether, our results suggest that a previously non-suspected function of RPA is to block cell cycle progression upon telomere uncapping using a yet unidentified pathway that functions in a Mec1-Ddc2-independent manner. We propose that in the rfa1 mutants, ill-masking of uncapped telomeres provokes inappropriate access of Tel1 and inappropriate functioning of telomerase, which, by yet unknown mechanisms, allows cell division to take place in spite of the block established by the DNA damage checkpoint. In the present study, we also observed that upon telomere uncapping, rfa1-12, but not the other studied rfa1 mutants, triggered telomeric recombination in the presence of functional telomerase. In conclusion, the present study identifies a novel pathway of telomere end protection that utilizes a previously unsuspected function of RPA at the telomeres.

Published
2014
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4. ATR-X mutations cause impaired nuclear location and altered DNA binding properties of the XNP/ATR-X protein

Author

Laurence Colleaux, Carlos Cardoso, Cecile Mignon, Michel Fontes, Yves Lutz, Emmanuel Compe, Marie-Geneviève Mattei, Danielle Depetris, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), INSERM U491 (U491), and COLLEAUX, Laurence

Subjects
Male, Mutant, Fluorescent Antibody Technique, Gene Expression, MESH: DNA Helicases, medicine.disease_cause, MESH: Thalassemia, MESH: Antibodies, Monoclonal, Epitopes, Exon, Antibody Specificity, MESH: Syndrome, Nuclear protein, MESH: Fluorescent Antibody Technique, Cells, Cultured, Genetics (clinical), Genetics, Zinc finger, Mutation, MESH: X-linked Nuclear Protein, MESH: DNA, Antibodies, Monoclonal, Nuclear Proteins, Zinc Fingers, Syndrome, DNA-Binding Proteins, Thalassemia, Protein Binding, MESH: Cells, Cultured, MESH: Cell Nucleus, X-linked Nuclear Protein, MESH: Epitopes, MESH: Gene Expression, MESH: Mutation, Blotting, Western, Active Transport, Cell Nucleus, MESH: Active Transport, Cell Nucleus, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, DNA-binding protein, Double-stranded DNA binding, MESH: Intellectual Disability, Intellectual Disability, medicine, Humans, MESH: Zinc Fingers, MESH: Blotting, Western, MESH: Protein Binding, MESH: Antibody Specificity, Gene, Cell Nucleus, MESH: Humans, DNA Helicases, Original Articles, DNA, Molecular biology, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins
Abstract

Mutations in the XNP/ATR-X gene, located in Xq13.3, are associated with several X linked mental retardation syndromes, the best known being α thalassaemia with mental retardation (ATR-X). The XNP/ATR-X protein belongs to the family of SWI/SNF DNA helicases and contains three C2-C2 type zinc fingers of unknown function. Previous studies have shown that 65% of mutations of XNP have been found within the zinc finger domain (encoded by exons 7, 8, and the beginning of exon 9) while 35% of the mutations have been found in the helicase domain extending over 3 kb at the C-terminus of the protein. Although different types of mutations have been identified, no specific genotype-phenotype correlation has been found, suggesting that gene alteration leads to a loss of function irrespective of mutation type. Our aims were to understand the function of the XNP/ATR-X protein better, with specific attention to the functional consequences of mutations to the zinc finger domain. We used monoclonal antibodies directed against the XNP/ATR-X protein and performed immunocytochemical and western blot analyses, which showed altered or absent XNP/ATR-X expression in cells of affected patients. In addition, we used in vitro experiments to show that the zinc finger domain can mediate double stranded DNA binding and found that the DNA binding capacity of mutant forms in ATR-X patients is severely reduced. These data provide insights into the understanding of the functional significance of XNP/ATR-X mutations. Keywords: XNP/ATR-X; mutation; zinc finger; DNA binding activity

Published
2000

5. Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein

Author

Laurent Villard, Serge Timsit, Laurence Colleaux, Carlos Cardoso, Michel Khrestchatisky, Michel Fontes, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Polycomb-Group Proteins, MESH: DNA Helicases, 0302 clinical medicine, Drosophila Proteins, Tissue Distribution, MESH: Animals, Genetics (clinical), In Situ Hybridization, Genetics, Regulation of gene expression, Polycomb Repressive Complex 1, 0303 health sciences, MESH: X-linked Nuclear Protein, Polycomb Repressive Complex 2, Nuclear Proteins, Zinc Fingers, General Medicine, MESH: Transcription Factors, MESH: Gene Expression Regulation, MESH: Saccharomyces cerevisiae, Chromatin, DNA-Binding Proteins, MESH: beta-Galactosidase, MESH: Repressor Proteins, 030220 oncology & carcinogenesis, Chromosome breakage, MESH: Polycomb Repressive Complex 2, MESH: Polycomb Repressive Complex 1, X-linked Nuclear Protein, MESH: Rats, DNA repair, MESH: Drosophila Proteins, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Biology, DNA-binding protein, Gene product, 03 medical and health sciences, MESH: In Situ Hybridization, Proto-Oncogene Proteins, Polycomb-group proteins, MESH: Recombinant Fusion Proteins, Animals, Humans, MESH: Zinc Fingers, MESH: Tissue Distribution, Molecular Biology, Gene, 030304 developmental biology, MESH: Humans, DNA Helicases, beta-Galactosidase, Rats, Repressor Proteins, MESH: Proto-Oncogene Proteins, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Nuclear Proteins, MESH: Polycomb-Group Proteins, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

International audience; Mutations in the XNP gene result in different inherited disorders, including the ATR-X syndrome which is characterized by mental retardation (MR) associated with alpha-thalaessemia. Amino acid sequence analysis revealed that the XNP protein is a new member of the SNF2-like family, which comprises numerous members involved in a broad range of biological functions: transcriptional regulation, DNA repair and chromosome segregation. Since experiments on fibroblasts from ATR-X patients have provided no evidence for either a DNA repair defect or abnormal chromosome breakage or segregation, it seems more likely that the XNP protein is somehow involved in regulation of gene expression. Recent genetic and biochemical studies have led to the emerging concept that SNF2-like proteins are components of a large protein complex which may exert its functions by modulating chromatin structure. To investigate whether XNP could mediate the activity of gene-specific activators through chromatin remodelling, we performed a yeast two-hybrid analysis using XNP and several human heterochromatin-associated proteins. We found a specific interaction between the XNP and the EZH2 proteins. In light of these observations, we discuss how the XNP protein may regulate gene transcription at the chromatin level.

Published
1998

6. Determination of the Genomic Structure of the XNP/ATRX Gene Encoding a Potential Zinc Finger Helicase

Author

Carlos Cardoso, V. Proud, Michel Fontes, Charles E. Schwartz, Pierre Chiaroni, Laurent Villard, Anne-Marie Lossi, Laurence Colleaux, Greenwood Genetic Center [Greenwood, South Carolina, USA], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Sequence Analysis, DNA, Transcription, Genetic, MESH: Introns, Restriction Mapping, MESH: DNA Helicases, MESH: Amino Acid Sequence, Polymerase Chain Reaction, Exon, Coding region, MESH: Syndrome, MESH: Restriction Mapping, Electrophoresis, Agar Gel, Genetics, Zinc finger, 0303 health sciences, Splice site mutation, MESH: X-linked Nuclear Protein, MESH: Alternative Splicing, 030305 genetics & heredity, Nuclear Proteins, Zinc Fingers, Exons, Syndrome, MESH: alpha-Thalassemia, Polyglutamic Acid, RNA splicing, X-linked Nuclear Protein, X Chromosome, MESH: Mutation, Molecular Sequence Data, Biology, MESH: Intellectual Disability, 03 medical and health sciences, alpha-Thalassemia, Intellectual Disability, Humans, MESH: Zinc Fingers, Amino Acid Sequence, RNA, Messenger, ATRX, 030304 developmental biology, MESH: RNA, Messenger, MESH: Molecular Sequence Data, MESH: X Chromosome, MESH: Humans, MESH: Transcription, Genetic, Alternative splicing, DNA Helicases, Intron, MESH: Polyglutamic Acid, MESH: Polymerase Chain Reaction, Sequence Analysis, DNA, Introns, Alternative Splicing, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, MESH: Electrophoresis, Agar Gel, MESH: Exons, MESH: Nuclear Proteins
Abstract

International audience; The XNP/ATR-X gene is involved in several X-linked mental retardation phenotypes: the ATR-X syndrome, the Juberg-Marsidi syndrome, and some severe mental retardation phenotypes without alpha-thalassemia. Using a vectorette strategy, we have identified and sequenced the intron/exon boundaries of this gene. The gene is composed of 35 exons. It encodes a potential protein of 2492 amino acids. A search of the databases identified three zinc finger motifs within the 5' end of the gene. Expression analysis in different tissues indicated that an alternative splicing event that involves exon 6 is occurring. One of these alternatively spliced transcripts is predominantly expressed in embryonic tissues. These data led us to search for mutations in the 5' region in ATRX patients without other mutations in the 3' region. In one patient a mutation was found in which part of exon 7 was removed from the XNP transcript, as a result of a mutation creating a novel splice site that is substituted for the natural splice site. This new splicing event removed one zinc finger motif. This is the first example of a mutation in XNP within the 5' coding region. It suggests that mutations will be predominantly found in the helicase region as well as in the zinc finger regions and leads us to propose a large screening of additional patients.

Published
1997
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