Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome

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 divisio...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2013-09, Vol.110 (36), p.14518-14518
Hauptverfasser: Deng, Zhong, Glousker, Galina, Molczan, Aliah, Fox, Alan J., Lamm, Noa, Dheekollu, Jayaraju, Weizman, Orr-El, Schertzer, Michael, Wang, Zhuo, Vladimirova, Olga, Schug, Jonathan, Aker, Memet, Londoño-Vallejo, Arturo, Kaestner, Klaus H., Lieberman, Paul M., Tzfati, Yehuda
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container_end_page 14518
container_issue 36
container_start_page 14518
container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 110
creator Deng, Zhong
Glousker, Galina
Molczan, Aliah
Fox, Alan J.
Lamm, Noa
Dheekollu, Jayaraju
Weizman, Orr-El
Schertzer, Michael
Wang, Zhuo
Vladimirova, Olga
Schug, Jonathan
Aker, Memet
Londoño-Vallejo, Arturo
Kaestner, Klaus H.
Lieberman, Paul M.
Tzfati, Yehuda
description 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.
doi_str_mv 10.1073/pnas.1300600110
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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. 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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. 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Glousker, Galina ; Molczan, Aliah ; Fox, Alan J. ; Lamm, Noa ; Dheekollu, Jayaraju ; Weizman, Orr-El ; Schertzer, Michael ; Wang, Zhuo ; Vladimirova, Olga ; Schug, Jonathan ; Aker, Memet ; Londoño-Vallejo, Arturo ; Kaestner, Klaus H. ; Lieberman, Paul M. ; Tzfati, Yehuda</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-e5492068b96e43844e65c92e535f19b2051de7554740ebe2d92182a14c4afec33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Base Sequence</topic><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>Blotting, Western</topic><topic>Cell division</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>DNA damage</topic><topic>DNA Helicases - genetics</topic><topic>DNA Helicases - metabolism</topic><topic>Dyskeratosis Congenita - genetics</topic><topic>Dyskeratosis Congenita - metabolism</topic><topic>Dyskeratosis Congenita - pathology</topic><topic>Enzymes</topic><topic>Family Health</topic><topic>Female</topic><topic>Fetal Growth Retardation - genetics</topic><topic>Fetal Growth Retardation - metabolism</topic><topic>Fetal Growth Retardation - pathology</topic><topic>Gene Expression</topic><topic>Genomic Instability - genetics</topic><topic>Genomics</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Intellectual Disability - genetics</topic><topic>Intellectual Disability - metabolism</topic><topic>Intellectual Disability - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Microcephaly - genetics</topic><topic>Microcephaly - metabolism</topic><topic>Microcephaly - pathology</topic><topic>Mutation</topic><topic>Pedigree</topic><topic>PNAS Plus</topic><topic>PNAS PLUS: Significance Statements</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Telomere - genetics</topic><topic>Telomere Shortening - genetics</topic><topic>Telomeric Repeat Binding Protein 1 - genetics</topic><topic>Telomeric Repeat Binding Protein 1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Deng, Zhong</creatorcontrib><creatorcontrib>Glousker, Galina</creatorcontrib><creatorcontrib>Molczan, Aliah</creatorcontrib><creatorcontrib>Fox, Alan J.</creatorcontrib><creatorcontrib>Lamm, Noa</creatorcontrib><creatorcontrib>Dheekollu, Jayaraju</creatorcontrib><creatorcontrib>Weizman, Orr-El</creatorcontrib><creatorcontrib>Schertzer, Michael</creatorcontrib><creatorcontrib>Wang, Zhuo</creatorcontrib><creatorcontrib>Vladimirova, Olga</creatorcontrib><creatorcontrib>Schug, Jonathan</creatorcontrib><creatorcontrib>Aker, Memet</creatorcontrib><creatorcontrib>Londoño-Vallejo, Arturo</creatorcontrib><creatorcontrib>Kaestner, Klaus H.</creatorcontrib><creatorcontrib>Lieberman, Paul M.</creatorcontrib><creatorcontrib>Tzfati, Yehuda</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium &amp; 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subjects Animals
Base Sequence
Binding sites
Biological Sciences
Blotting, Western
Cell division
Cell Proliferation
Cells, Cultured
DNA damage
DNA Helicases - genetics
DNA Helicases - metabolism
Dyskeratosis Congenita - genetics
Dyskeratosis Congenita - metabolism
Dyskeratosis Congenita - pathology
Enzymes
Family Health
Female
Fetal Growth Retardation - genetics
Fetal Growth Retardation - metabolism
Fetal Growth Retardation - pathology
Gene Expression
Genomic Instability - genetics
Genomics
HeLa Cells
Humans
In Situ Hybridization, Fluorescence
Intellectual Disability - genetics
Intellectual Disability - metabolism
Intellectual Disability - pathology
Male
Mice
Microcephaly - genetics
Microcephaly - metabolism
Microcephaly - pathology
Mutation
Pedigree
PNAS Plus
PNAS PLUS: Significance Statements
Reverse Transcriptase Polymerase Chain Reaction
Telomere - genetics
Telomere Shortening - genetics
Telomeric Repeat Binding Protein 1 - genetics
Telomeric Repeat Binding Protein 1 - metabolism
title Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome
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