The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.
Bibliographical noteFunding Information:
National Institute on Aging-funded pre-doctoral fellowship [T32 AG029796 to S.S.]; National Institutes of General Medicine [GM088351 to E.A.H.]; National Cancer Institute [CA154461 to E.A.H.]. Funding for open access charge: National Institute on Aging-funded pre-doctoral fellowship [T32 AG029796 to S.S.]; National Institutes of General Medicine [GM088351 to E.A.H.]; National Cancer Institute [CA154461 to E.A.H.]. Conflict of interest statement. E.A.H. sits on the Scientific Advisory Boards of Horizon Discovery, Ltd and Intellia Therapeutics.
© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.