Perspectives on PARPs in S Phase

PARP1 and PARP2 are essential for embryonic viability, and chemical inhibition of these enzymes in the clinic selectively kills homologous recombination-defective cancer cells (e.g., those harbouring mutations in BRCA1 or BRCA2). PARP1 and PARP2 are activated by potentially pathogenic nucleic acid structures such as DNA breaks, DNA single-strand gaps, and stalled or broken DNA replication forks. PARP activity signals the presence of these structures by modifying themselves and other proteins with poly(ADP-ribose), thereby promoting their repair. Unligated Okazaki fragment DNA replication intermediates are primary inducers of PARP activity in normal proliferating cells. Unligated Okazaki fragments are candidate drivers of genome instability and/or cell death in developing embryos and in homologous recombination-defective cancer cells in which PARP activity is absent or inhibited