The multifaceted roles of PARP1 in DNA repair and chromatin remodelling

Key Points Poly(ADP-ribose) polymerase 1 (PARP1) was the first member of the PARP family to be identified. The PARP family now comprises 18 members. PARP1 post-translationally modifies itself and a range of other proteins that have diverse roles in different cellular processes. The catalytic activity of PARP1 is responsible for mediating multiple DNA damage repair pathways. PARP1 has a crucial role in the stabilization of DNA replication forks. The role of PARP1 in remodelling chromatin overlaps with its role in DNA repair. PARP1 inhibition is an attractive strategy for the treatment of cancers that are deficient in the repair of DNA double-strand breaks by homologous recombination. Recent insights into the roles of poly(ADP-ribose) polymerase 1 (PARP1) in mediating various DNA repair pathways, stabilizing DNA replication and modulating chromatin structure are being exploited clinically for the treatment of DNA repair-deficient cancers. Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers. Understanding the role of PARP1 in maintaining genome integrity is not only important for the design of novel chemotherapeutic agents, but is also crucial for gaining insights into the mechanisms of chemoresistance in cancer cells. In this Review, we discuss the roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-strand break repair and the stabilization of replication forks, and in modulating chromatin structure.