Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension

Rosa M. Porreca, Galina Glousker, Aya Awad, Maria I. Matilla Fernandez, Anne Gibaud, Christian Naucke, Scott B. Cohen, Tracy M. Bryan, Yehuda Tzfati, Irena Draskovic, Arturo Londoño-Vallejo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase.

Original languageAmerican English
Pages (from-to)4533-4545
Number of pages13
JournalNucleic Acids Research
Volume46
Issue number9
StatePublished - 2018

Bibliographical note

Funding Information:
Institut Curie and from Fondation ARC Fellowship (to R.M.P.); Agence Nationale pour la Recherche [ANR-14-CE10-0006-01 to A.L.V., in part]; Israel Science Foundation [1729/13 to Y.T.]; Israel Cancer Research Fund (to Y.T.); Worldwide Cancer Research [15-0338 to Y.T.]; Cancer Council NSW [RG 16-10 to T.M.B.]. Funding for open access charge: Institut Curie.

Funding Information:
Institut Curie and from Fondation ARC Fellowship (to R.M.P.); Agence Nationale pour la Recherche [ANR-14- CE10-0006-01 to A.L.V., in part]; Israel Science Foundation [1729/13 to Y.T.]; Israel Cancer Research Fund (to Y.T.); Worldwide Cancer Research [15-0338 to Y.T.]; Cancer Council NSW [RG 16-10 to T.M.B.]. Funding for open access charge: Institut Curie. Conflict of interest statement. None declared.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

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