CtIP is essential for telomere replication

Abstract

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.

Extrachromosomal Circular DNA: Current Knowledge and Implications for CNS Aging and Neurodegeneration

“…A further factor essential for telomere replication, which operates in association with the MRE11-RAD50-NBS1 (MRN) complex, is the C-terminal binding protein (CtBP)-interacting protein (CtIP). Absence of this DNA-repair protein leads to a drastic reduction of telomere length, increased generation of T-circles, DNA damage and chromosomal aberrations [81]. A similar role in telomere replication, maintenance and repair applies to SAE2, the yeast homolog of CtIP [82][83][84].…”

“…Interestingly, the inducible loss of CtIP, as investigated in hTERT-immortalized epithelial RPE1 cells derived from the retina, leads to the accumulation of T-circles but not of C-circles [81], the second of which has recently been established as a specific marker of ALT [85]. However, silencing of CtIP in the ALT-positive U2OS cell line resulted in a two-fold increment in C-circles, inferring that CtIP protects telomeres in both scenarios, i.e., a telomerase-positive as well as an ALT-positive environment, and suppressed the release of ECTRs [81].…”

DNA Replication proteins in primary microcephaly syndromes

“…Retinoblastoma‐binding protein 8 (RBBP8), better known as CtIP, has been found to be essential for this end resection (Sartori et al., 2007). Interestingly, CtIP also governs replication of telomere sequences (Stroik et al., 2019) and is involved in maintenance of stalled replication forks (Przetocka et al., 2018). If such resection of a broken end occurs, NHEJ can no longer repair the lesion.…”

Telomere Maintenance and the cGAS-STING Pathway in Cancer

“…These 3′-overhangs enable the strand invasion necessary for HR. As both ATM and CtIP are involved in telomere maintenance [ 101 , 102 ], it is tempting to speculate that the ALT pathway relies on the MRN complex-mediated HR machinery. In contrast, the active ATM monomer phosphorylates histone H2AX at the DNA lesion, which prevents CtIP-dependent end-resection [ 103 , 104 ].…”