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 itssynthetic lethality with breast cancer allele 1 and 2 mutations, which are causativefor inherited breast and ovarian cancers. Biochemically, PARP1 is a single-strandedDNA break repair protein that is needed for preserving genomic integrity. In addition,PARP1 has been implicated in a veritable plethora of additional cellular pathwaysand thus its precise contribution(s) to human biology has remained obscure. To helpaddress this deficiency, we utilized gene editing to construct genetically-null PARP1human cancer cells. We found a minor role for PARP1 in an alternative form of DNAdouble-strand break (DSB) repair, but only when these cells were deficient for theclassical form of DSB repair. Despite being proficient for DSB repair, however, cellcycle progression defects and elevated endogenous DNA damage signaling wereobserved. These deficiencies were instead linked to telomere defects, where PARP1-/-cells had short telomeres that co-localized with markers of endogenous DNA damageand were compromised in their ability to escape a telomere-driven crisis. Our datasuggest 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 genomicinstability.