Poly ADP-ribose polymerases (PARPs) catalyze massive protein poly ADP-ribosylation (PARylation) within seconds after the induction of DNA single- or double-strand breaks. PARylation occurs at or near the sites of DNA damage and promotes the recruitment of DNA repair factors via their poly ADP-ribose (PAR) binding domains. Several novel PAR-binding domains have been recently identified. Here, we summarize these and other recent findings suggesting that PARylation may be the critical event that mediates the first wave of the DNA damage response. We also discuss the potential for functional crosstalk with other DNA damage-induced post-translational modifications.

ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD+ as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers. Here, we show that ovarian cancer cells with higher level of NADP+, an NAD+ derivative, are more sensitive to PARP inhibitors. We demonstrate that NADP+ acts as a negative regulator and suppresses ADP-ribosylation both in vitro and in vivo. NADP+ impairs ADP-ribosylation-dependent DNA damage repair and sensitizes tumor cell to chemically synthesized PARP inhibitors. Taken together, our study identifies NADP+ as an endogenous PARP inhibitor that may have implications in cancer treatment.