PARP-1 and its associated nucleases in DNA damage response.

Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) acts as a DNA damage sensor. It recognizes DNA damage and facilitates DNA repair by recruiting DNA repair machinery to damage sites. Recent studies reported that PARP-1 also plays an important role in DNA replication by recognizing the unligated Okazaki fragments and controlling the speed of fork elongation. On the other hand, emerging evidence reveals that excessive activation of PARP-1 causes chromatin DNA fragmentation and triggers an intrinsic PARP-1-dependent cell death program designated parthanatos, which can be blocked by genetic deletion or pharmacological inhibition of PARP-1. Therefore, PARP-1 plays an essential role in maintaining genomic stability by either facilitating DNA repair/replication or triggering DNA fragmentation to kill cells. A group of structure-specific nucleases is crucial for executing DNA incision and fragmentation following PARP-1 activation. In this review, we will discuss how PARP-1 coordinates with its associated nucleases to maintain genomic integrity and control the decision of cell life and death.