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1. Human RTEL1 Interacts with KPNB1 (Importin β) and NUP153 and Connects Nuclear Import to Nuclear Envelope Stability in S-Phase

Author

Michael Schertzer, Laurent Jullien, André L. Pinto, Rodrigo T. Calado, Patrick Revy, and Arturo Londoño-Vallejo

Subjects
Regulator of TElomere Length Helicase 1, protein import, nuclear envelope, nuclear pore, KPNB1 (importin β), NUP153, Cytology, QH573-671
Abstract

Regulator of TElomere Length Helicase 1 (RTEL1) is a helicase required for telomere maintenance and genome replication and repair. RTEL1 has been previously shown to participate in the nuclear export of small nuclear RNAs. Here we show that RTEL1 deficiency leads to a nuclear envelope destabilization exclusively in cells entering S-phase and in direct connection to origin firing. We discovered that inhibiting protein import also leads to similar, albeit non-cell cycle-related, nuclear envelope disruptions. Remarkably, overexpression of wild-type RTEL1, or of its C-terminal part lacking the helicase domain, protects cells against nuclear envelope anomalies mediated by protein import inhibition. We identified distinct domains in the C-terminus of RTEL1 essential for the interaction with KPNB1 (importin β) and NUP153, respectively, and we demonstrated that, on its own, the latter domain can promote the dynamic nuclear internalization of peptides that freely diffuse through the nuclear pore. Consistent with putative functions exerted in protein import, RTEL1 can be visualized on both sides of the nuclear pore using high-resolution microscopy. In all, our work points to an unanticipated, helicase-independent, role of RTEL1 in connecting both nucleocytoplasmic trafficking and nuclear envelope integrity to genome replication initiation in S-phase.

Published
2023
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3. 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
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5. Human regulator of telomere elongation helicase 1 (RTEL1) is required for the nuclear and cytoplasmic trafficking of pre-U2 RNA

Author

Arturo Londoño-Vallejo, Michael Schertzer, Florent Dingli, Patrick Revy, Tangui Le Guen, Mylène Perderiset, Barbara Bardoni, Damarys Loew, Jean-Pierre de Villartay, Karina Jouravleva, Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris sciences et lettres (PSL), Telomeres and Cancer Laboratory (Lab ellis e Ligue), Telomeres and Cancer Laboratory, Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis - Faculté des Sciences (UNS UFR Sciences), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), 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)-Université Côte d'Azur (UCA), PSL Research University (PSL), Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Pierre et Marie Curie - Paris 6 ( UPMC ), PSL Research University ( PSL ), INSTITUT CURIE, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Nice Sophia Antipolis - Faculté des Sciences ( UNS UFR Sciences ), and Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA )

Subjects
Cytoplasm, medicine.disease_cause, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Tandem Mass Spectrometry, RNA, Small Nuclear, RNA Precursors, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Small Interfering, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, DNA Primers, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, biology, HEK 293 cells, DNA Helicases, Helicase, RNA, Biological Transport, Blotting, Northern, medicine.disease, Molecular biology, Telomere, Cell nucleus, HEK293 Cells, medicine.anatomical_structure, RNA splicing, biology.protein, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, 030217 neurology & neurosurgery, Dyskeratosis congenita, Chromatography, Liquid, HeLa Cells
Abstract

Hoyeraal-Hreidarsson syndrome (HHS) is a severe form of Dyskeratosis congenita characterized by developmental defects, bone marrow failure and immunodeficiency and has been associated with telomere dysfunction. Recently, mutations in Regulator of Telomere ELongation helicase 1 (RTEL1), a helicase first identified in Mus musculus as being responsible for the maintenance of long telomeres, have been identified in several HHS patients. Here we show that RTEL1 is required for the export and the correct cytoplasmic trafficking of the small nuclear (sn) RNA pre-U2, a component of the major spliceosome complex. RTEL1-HHS cells show abnormal subcellular partitioning of pre-U2, defects in the recycling of ribonucleotide proteins (RNP) in the cytoplasm and splicing defects. While most of these phenotypes can be suppressed by re-expressing the wild-type protein in RTEL1-HHS cells, expression of RTEL1 mutated variants in immortalized cells provokes cytoplasmic mislocalizations of pre-U2 and other RNP components, as well as splicing defects, thus phenocopying RTEL1-HHS cellular defects. Strikingly, expression of a cytoplasmic form of RTEL1 is sufficient to correct RNP mislocalizations both in RTEL1–HHS cells and in cells expressing nuclear mutated forms of RTEL1. This work unravels completely unanticipated roles for RTEL1 in RNP trafficking and strongly suggests that defects in RNP biogenesis pathways contribute to the pathology of HHS.

Published
2015
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6. Extension of Cell Life-Span and Telomere Length in Animals Cloned from Senescent Somatic Cells

Author

Nancy Sawyer, Jennifer Mak, Catherine Blackwell, Jose B. Cibelli, Gabriela M. Baerlocher, Elizabeth A. Chavez, Mary Kay Francis, Michael D. West, Vincent J. Cristofalo, Robert Lanza, Peter M. Lansdorp, and Michael Schertzer

Subjects
Senescence, Nuclear Transfer Techniques, DNA, Complementary, Somatic cell, Cloning, Organism, Matched-Pair Analysis, Longevity, Cell, Population, Biology, Andrology, Gene expression, medicine, Animals, Nerve Growth Factors, RNA, Messenger, Eye Proteins, education, Cells, Cultured, Cellular Senescence, In Situ Hybridization, Fluorescence, Serpins, Southern blot, Cloning, education.field_of_study, Multidisciplinary, Proteins, Fibroblasts, Telomere, Embryo Transfer, Flow Cytometry, Molecular biology, Clone Cells, Blotting, Southern, medicine.anatomical_structure, Cattle, Female, Cell Division
Abstract

The potential of cloning depends in part on whether the procedure can reverse cellular aging and restore somatic cells to a phenotypically youthful state. Here, we report the birth of six healthy cloned calves derived from populations of senescent donor somatic cells. Nuclear transfer extended the replicative life-span of senescent cells (zero to four population doublings remaining) to greater than 90 population doublings. Early population doubling level complementary DNA-1 (EPC-1, an age-dependent gene) expression in cells from the cloned animals was 3.5- to 5-fold higher than that in cells from age-matched (5 to 10 months old) controls. Southern blot and flow cytometric analyses indicated that the telomeres were also extended beyond those of newborn (

Published
2000
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7. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome

Author

Zhuo Wang, Michael Schertzer, Noa Lamm, Olga Vladimirova, Yehuda Tzfati, Klaus H. Kaestner, Memet Aker, Jonathan Schug, Jayaraju Dheekollu, Paul M. Lieberman, Alan J. Fox, Galina Glousker, Orr-El Weizman, Zhong Deng, Aliah Molczan, and Arturo Londoño-Vallejo

Subjects
Genome instability, Male, Telomerase, Blotting, Western, Gene Expression, Hoyeraal-Hreidarsson syndrome, Biology, medicine.disease_cause, Dyskeratosis Congenita, Genomic Instability, Mice, Intellectual Disability, medicine, Animals, Humans, Telomeric Repeat Binding Protein 1, Cells, Cultured, In Situ Hybridization, Fluorescence, Telomere Shortening, Cell Proliferation, Genetics, Family Health, Mutation, Multidisciplinary, Fetal Growth Retardation, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, DNA Helicases, Telomere, medicine.disease, Shelterin, Pedigree, PNAS Plus, Microcephaly, Female, Dyskeratosis congenita, HeLa Cells
Abstract

Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal–Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres.

Published
2013

8. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability

Author

Tangui Le Guen, Gérard Couillault, Laetitia Gaillard, Jean Soulier, Capucine Picard, Jean-Pierre de Villartay, Fabien Touzot, Patrick Nitschke, Isabelle Callebaut, Arturo Londoño-Vallejo, Michael Schertzer, Nada Jabado, Alain Fischer, Mylène Perderiset, Wassila Carpentier, Patrick Revy, Laurent Jullien, Thomas, Danielle, Centre de recherche en Biologie Cellulaire (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Telomeres and Cancer Laboratory, Institut Curie [Paris], Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pédiatrie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de pediatrie, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-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 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), and Department of Human Genetics

Subjects
Genome instability, DNA Replication, Male, DNA damage, DNA repair, Genetic Linkage, Hoyeraal-Hreidarsson syndrome, Biology, medicine.disease_cause, Dyskeratosis Congenita, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Exome, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Telomerase, Genetics (clinical), Cells, Cultured, Telomere Shortening, 030304 developmental biology, 0303 health sciences, Mutation, Fetal Growth Retardation, Sequence Analysis, RNA, DNA replication, DNA Helicases, Infant, Telomere Homeostasis, General Medicine, Telomere, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Child, Preschool, Microcephaly, Female, Sequence Alignment, Dyskeratosis congenita, DNA Damage
Abstract

International audience; Hoyeraal-Hreidarsson syndrome (HHS), a severe variant of dyskeratosis congenita (DC), is characterized by early onset bone marrowfailure, immunodeficiency and developmental defects. Several factors involved in telomere length maintenance and/or protection are defective in HHS/DC, underlining the relationship between telomeredysfunctionandthese diseases.Bycombining whole-genomelinkage analysisandexomesequencing,we identified compound heterozygous RTEL1 (regulator of telomere elongation helicase 1) mutations in three patients with HHS from two unrelated families. RTEL1 is a DNA helicase that participates in DNA replication, DNA repair and telomere integrity. We show that, in addition to short telomeres, RTEL1-deficient cells from patients exhibit hallmarks of genome instability, including spontaneous DNA damage, anaphase bridges and telomeric aberrations. Collectively, these results identify RTEL1 as a novel HHS-causing gene and highlight its role as a genomic caretaker in humans.

Published
2013
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9. Mapping of the Pulmonary Surfactant SP5 (SFTP2) Locus to 8p21 and Characterization of a Microsatellite Repeat Marker That Shows Frequent Loss of Heterozygosity in Human Carcinomas

Author

Pond R. Kelemen, John D. Minna, M.Lisa Yaremko, Michael Schertzer, Carol A. Westbrook, and Stephen Wood

Subjects
Genetic Markers, Heterozygote, Genetic Linkage, Molecular Sequence Data, Locus (genetics), DNA, Satellite, Gene mutation, Biology, Polymerase Chain Reaction, Loss of heterozygosity, Gene mapping, Neoplasms, Complementary DNA, Microsatellite Repeat, Genetics, Humans, Alleles, In Situ Hybridization, Fluorescence, Repetitive Sequences, Nucleic Acid, Base Sequence, DNA–DNA hybridization, Chromosome Mapping, Pulmonary Surfactants, Cosmids, Molecular biology, Cosmid, Chromosomes, Human, Pair 8
Abstract

We have identified 4 cosmids at the SFTP2 locus by cDNA hybridization. SFTP2 was mapped using a polymorphic CA repeat and localized to 8p21 by FISH. Allele loss in carcinomas was detected using this PCR marker. Among 11 lung and colon tumors, 6 of 9 informative cases exhibited allelic loss.

Published
1994
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10. High incidence of rapid telomere loss in telomerase-deficient Caenorhabditis elegans

Author

Peter M. Lansdorp, Iris Cheung, Ann M. Rose, and Michael Schertzer

Subjects
Telomerase, DNA Repair, Mutant, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Telomerase RNA component, Genetics, medicine, Animals, Telomerase reverse transcriptase, Caenorhabditis elegans, 030304 developmental biology, Telomere-binding protein, 0303 health sciences, Mutation, 030302 biochemistry & molecular biology, Telomere, biology.organism_classification, DNA-Binding Proteins, Kinetics, Gene Deletion
Abstract

Telomerase is essential to maintain telomere length in most eukaryotes. Other functions for telomerase have been proposed but molecular mechanisms remain unclear. We studied Caenorhabditis elegans with a mutation in the trt-1 telomerase reverse transcriptase gene. Mutant animals showed a progressive decrease in brood size and typically failed to reproduce after five generations. Using PCR analysis to measure the length of individual telomere repeat tracks on the left arm of chromosome V we observed that trt-1 mutants lost approximately 125bp of telomeric DNA per generation. Chromosome fusions involving complex recombination reactions were observed in late generations. Strikingly, trt-1 mutant animals displayed a high frequency of telomeres with many fewer repeats than average. Such outlying short telomeres were not observed in mrt-2 mutants displaying progressive telomere loss very similar to trt-1 mutants. We speculate that, apart from maintaining the average telomere length, telomerase is required to prevent or repair sporadic telomere truncations that are unrelated to the typical 'end-replication' problems.

Published
2006

11. Genomic organization, expression, and chromosome location of the human SNAIL gene (SNAI1) and a related processed pseudogene (SNAI1P)

Author

Stephen Wood, Kazuki Okajima, William A. Paznekas, Michael Schertzer, and Ethylin Wang Jabs

Subjects
Adult, Fetal Proteins, Male, animal structures, DNA, Complementary, Pseudogene, DNA Mutational Analysis, Molecular Sequence Data, Chromosomes, Human, Pair 20, Snail, Hybrid Cells, Cohort Studies, Mesoderm, Craniosynostoses, Embryonic and Fetal Development, Gene mapping, Species Specificity, biology.animal, parasitic diseases, Genetics, Morphogenesis, Animals, Humans, Amino Acid Sequence, Gene, Zebrafish, Genomic organization, Zinc finger, Expressed Sequence Tags, biology, Sequence Homology, Amino Acid, fungi, Zinc Fingers, Exons, biology.organism_classification, DNA-Binding Proteins, Drosophila melanogaster, Genes, Neural Crest, Organ Specificity, Chromosomes, Human, Pair 2, SNAI1, Vertebrates, Snail Family Transcription Factors, Sequence Alignment, Pseudogenes, Transcription Factors
Abstract

Some of the zinc finger proteins of the snail family are essential in the formation of mesoderm during gastrulation and the development of neural crest and its derivatives. We have isolated the human SNAIL gene (HGMW-approved symbol SNAI1) and describe its genomic organization, having sequenced a region spanning more than 5882 bp. The human SNAIL gene contains three exons. The SNAIL transcript is 2.0 kb and is found in placenta and adult heart, lung, brain, liver, and skeletal muscle. It codes for a protein of 264 amino acids and 29.1 kDa. This protein contains three classic zinc fingers and one atypical zinc finger. The human SNAIL protein is 87.5, 58.7, 50.9, 50.7, 55.4, and 31.5% identical to mouse Snail, chicken snail-like, zebrafish snail1, zebrafish snail2, Xenopus snail, and Drosophila snail proteins, respectively. The zinc finger region is 95.5% identical between human and mouse Snail. Because Drosophila snail and twist are important regulators during mesoderm development and because human TWIST mutations have been implicated in craniosynostosis, a cohort of 59 patients with craniosynostosis syndromes were screened for SNAIL mutations. None were found. By somatic cell and radiation hybrid mapping panels, SNAIL was localized to human chromosome 20q13.2, between markers D20S886 and D20S109. A SNAIL-related, putative processed pseudogene (HGMW-approved symbol SNAI1P) was also isolated and maps to human chromosome 2q33–q37.

Published
1999

12. Human SLUG gene organization, expression, and chromosome map location on 8q

Author

Ethylin Wang Jabs, Mingfei Yin, Stephen Wood, William A. Paznekas, Michael Schertzer, and Michael Cohen

Subjects
animal structures, Slug, Molecular Sequence Data, Xenopus, Polymerase Chain Reaction, Homology (biology), Exon, Limb bud, Gene expression, Genetics, Humans, Amino Acid Sequence, RNA, Messenger, Gene, Zinc finger, biology, Sequence Homology, Amino Acid, fungi, Chromosome Mapping, Gene Expression Regulation, Developmental, Zinc Fingers, Exons, Sequence Analysis, DNA, biology.organism_classification, Cosmids, Introns, Cell biology, DNA-Binding Proteins, embryonic structures, Snail Family Transcription Factors, Chromosomes, Human, Pair 8, Transcription Factors
Abstract

SLUG is a member of the snail family of zinc finger proteins. It is involved in epithelial to mesenchyme cell transition during neurulation and plays a role in limb bud development. We have isolated and described the human SLUG gene by sequencing a region spanning 4034 bp. The human SLUG gene contains three exons. The SLUG transcript is 2.2 kb and is found in placenta and adult heart, pancreas, liver, kidney, and skeletal muscle, and it codes for a protein of 268 amino acids and 29.989 kDa. This protein contains five zinc finger regions. The human SLUG protein is 95, 93, and 88% homologous to mouse, chicken, and Xenopus slug, respectively, but shows only 47% homology to mouse Snail. The zinc finger region is 100% identical between human and mouse Slug. Slug maps to the long arm of chromosome 8, closely linked to D8S2090 between D8S519 and D8S1098.

Published
1998

13. Support for founder effect for two lipoprotein lipase (LPL) gene mutations in French Canadians by analysis of GT microsatellites flanking the LPL gene

Author

Michael R. Hayden, Stephen Wood, Michael Schertzer, and Yuanhong Ma

Subjects
Adult, Male, Linkage disequilibrium, Canada, Population, DNA Mutational Analysis, Molecular Sequence Data, Biology, DNA, Satellite, Linkage Disequilibrium, Gene Frequency, Genetics, Humans, education, Child, Gene, Allele frequency, Genetics (clinical), Alleles, Repetitive Sequences, Nucleic Acid, education.field_of_study, Lipoprotein lipase, Chi-Square Distribution, Base Sequence, digestive, oral, and skin physiology, Haplotype, Quebec, nutritional and metabolic diseases, Molecular biology, Pedigree, Lipoprotein Lipase, Haplotypes, Mutation, Microsatellite, lipids (amino acids, peptides, and proteins), Female, Hyperlipoproteinemia Type I, France, Polymorphism, Restriction Fragment Length, Founder effect
Abstract

Mutations in the human lipoprotein lipase (LPL) gene are one of the major causes of familial chylomicronemia. We have characterized two polymorphic GT microsatellites flanking this gene. Two LPL mutations that are extremely frequent in French Canadians appear to be in complete linkage disequilibrium with specific LPL microsatellite haplotypes indicating a founder effect within this population.

Published
1993

14. Human chromosome 8 linkage map based on short tandem repeat polymorphisms: effect of genotyping errors

Author

Patricia Wilkie, James Tomfohrde, Stephen Wood, Michael J. Wagner, Michael Schertzer, Zhenyuan Wang, D. E. Wells, James L. Weber, L. A. Sadler, Stephen P. Daiger, Julia Parrish, and Susan H. Blanton

Subjects
Male, Genotype, Genetic Linkage, Molecular Sequence Data, Biology, Polymerase Chain Reaction, Gene mapping, Genetic linkage, Genetics, Humans, Crossing Over, Genetic, Genotyping, Alleles, Repetitive Sequences, Nucleic Acid, Linkage (software), Polymorphism, Genetic, Base Sequence, Chromosome, Chromosome Mapping, Genetic marker, Microsatellite, Female, Restriction fragment length polymorphism, Lod Score, Chromosomes, Human, Pair 8
Abstract

A linkage map consisting of 21 dinucleotide repeat polymorphisms, 1 tetranucleotide repeat polymorphism, and 3 RFLPs was constructed for human chromosome 8. The map spanned most of the chromosome length from near pter to q23-q24 on the distal portion of the long arm. The total 186 cM length of the female map was over two times the 84 cM length of the male map. Cytogenetic mapping of the polymorphisms using a panel of hybrids containing rearranged chromosomes was completely consistent with the linkage map. Special effort was made to remove as many genotyping errors, including parental phase errors, as possible. Removal of errors, in agreement with recent theoretical predictions, led to reduction of the total length of the sex-equal map by 10% from 145 to 130 cM.

Published
1992

15. Linkage mapping of the D8S133 locus to chromosome 8p using a highly informative, polymorphic, complex dinucleotide repeat

Author

Stephen Wood and Michael Schertzer

Subjects
Genetics, Genetic Markers, Polymorphism, Genetic, Base Sequence, Genetic Linkage, Chromosome 8p, Molecular Sequence Data, Chromosome Mapping, Locus (genetics), Biology, Dinucleotide Repeat, Gene mapping, Genetic linkage, Genetic marker, Humans, Restriction fragment length polymorphism, Allele frequency, Chromosomes, Human, Pair 8, Repetitive Sequences, Nucleic Acid
Published
1992

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