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: Zhong Deng, Galina Glousker, Aliah Molczan, Alan J Fox, Noa Lamm, Jayaraju Dheekollu, Orr-El Weizman, Michael Schertzer, Zhuo Wang, Olga Vladimirova, Jonathan Schug, Memet Aker, Arturo Londoño-Vallejo, Klaus H Kaestner, Paul M Lieberman, Yehuda Tzfati
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 36 Pg. E3408-16 (Sep 03 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23959892 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Telomeric Repeat Binding Protein 1
• RTEL1 protein, human
• DNA Helicases

Topics

• Animals
• Base Sequence
• Blotting, Western
• Cell Proliferation
• Cells, Cultured
• DNA Helicases (genetics, metabolism)
• Dyskeratosis Congenita (genetics, metabolism, pathology)
• Family Health
• Female
• Fetal Growth Retardation (genetics, metabolism, pathology)
• Gene Expression
• Genomic Instability (genetics)
• HeLa Cells
• Humans
• In Situ Hybridization, Fluorescence
• Intellectual Disability (genetics, metabolism, pathology)
• Male
• Mice
• Microcephaly (genetics, metabolism, pathology)
• Mutation
• Pedigree
• Reverse Transcriptase Polymerase Chain Reaction
• Telomere (genetics)
• Telomere Shortening (genetics)
• Telomeric Repeat Binding Protein 1 (genetics, metabolism)