title: Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome.
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.
authors: Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA 19104, USA.
authors: Zhong
authors: Z
authors: Deng
authors: Galina
authors: G
authors: Glousker
authors: Aliah
authors: A
authors: Molczan
authors: Alan J
authors: AJ
authors: Fox
authors: Noa
authors: N
authors: Lamm
authors: Jayaraju
authors: J
authors: Dheekollu
authors: Orr-El
authors: OE
authors: Weizman
authors: Michael
authors: M
authors: Schertzer
authors: Zhuo
authors: Z
authors: Wang
authors: Olga
authors: O
authors: Vladimirova
authors: Jonathan
authors: J
authors: Schug
authors: Memet
authors: M
authors: Aker
authors: Arturo
authors: A
authors: Londoño-Vallejo
authors: Klaus H
authors: KH
authors: Kaestner
authors: Paul M
authors: PM
authors: Lieberman
authors: Yehuda
authors: Y
authors: Tzfati
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005192:Family Health; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D042822:Genomic Instability / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016615:Telomere / Q000235:genetics*; D059506:Telomere Shortening / Q000235:genetics; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D035321:Telomeric Repeat Binding Protein 1; C532890:RTEL1 protein, human; D004265:DNA Helicases
keywords: aging; dyskeratosis congenita; genomic instability; telomeropathies
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