PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ

Abstract

Poly-ADP ribose polymerase 1 (PARP1) is clinically important because of its synthetic lethality with breast cancer allele 1 and 2 mutations, which are causative for inherited breast and ovarian cancers. Biochemically, PARP1 is a single-stranded DNA break repair protein that is needed for preserving genomic integrity. In addition, PARP1 has been implicated in a veritable plethora of additional cellular pathways and thus its precise contribution(s) to human biology has remained obscure. To help address this deficiency, we utilized gene editing to construct genetically-null PARP1 human cancer cells. We found a minor role for PARP1 in an alternative form of DNA double-strand break (DSB) repair, but only when these cells were deficient for the classical form of DSB repair. Despite being proficient for DSB repair, however, cell cycle progression defects and elevated endogenous DNA damage signaling were observed. These deficiencies were instead linked to telomere defects, where PARP1−/− cells had short telomeres that co-localized with markers of endogenous DNA damage and were compromised in their ability to escape a telomere-driven crisis. Our data suggest that while PARP1 does not participate significantly in DNA DSB repair itself, it does prevent the incidence of telomeric DSBs, which, in turn, can drive genomic instability.

Intimate Relations—Mitochondria and Ageing

“…In addition to repairing strand breaks in DNA, PARP activity may also be required for the maintenance of telomeres, the repetitive DNA structures found at the ends of chromosomes [ 154 , 155 , 156 , 157 ]. Telomere shortening occurs through life, has been shown to be the cause of the replication exhaustion of populations such as fibroblasts (first described by Hayflick and Moorhead in 1961) [ 158 ] and has been proposed as a risk factor for age related diseases [ 159 , 160 ].…”

Both the classical and alternative non-homologous end joining pathways contribute to the fusion of drastically shortened telomeres induced by TRF2 overexpression

“…There is precedence for this in at least the case of crisis-induced fusion events [32,33]. Several constituents of the DNA damage repair pathways, such as the Ku complex [5,[34][35][36], WRN [37], PARP1 [38][39][40], and DNA polymerase theta [41], have been reported to affect C-and A-NHEJ choices at damaged telomeres. A subject for future study is to understand the contribution of each to TRF2 overexpression-induced fusions.…”

PARP inhibition prevents escape from a telomere-driven crisis and inhibits cell immortalisation

“…PARPi such as rucaparib and olaparib can also inhibit the activities of other PARP family members to a lesser extent [36, 37]. However, our recent observation that deletion of PARP1 also strongly prevents HCT116 from escaping a telomere crisis [38] suggest that instead of inducing PARP1 trapping or inhibiting other PARP family members, PARPi prevent escape from crisis mainly by inhibiting PARP1.…”

“…Alternatively, it is also possible that PARPi inhibit escape from a telomere crisis independently of LIG3. PARP1 has been implicated in telomere maintenance and PARP1 deficient cells have short telomeres and increased telomeric DNA damage [38, 43, 44]. It was shown recently that a PARP inhibitor (3-AB) inhibits the growth of pancreatic cancer cells treated with a telomerase inhibitor by inducing telomere shortening through the inhibition of Tankyrases [45].…”