FIGURE 2.

Mechanism and function of PARP and PARP inhibitors. The catalytic function of PARP1 is activated through binding to the SSBs site cuased by alkylating agents. Activated PARP1 undergo PARylation and recruitment of a serials of key DNA repair effectors involved in BER to repair DNA lesion. Finally, PARP1 release from DNA and regain inactive state. PARP inhibitors binds the catalytic site of PARP and impaired of the enzymatic activity of PARP which “trap” PARP1 on DNA, results in suppression of the catalytic cycle of PARP1 and BER. Trapping PARP1 on DNA lesion also collapses DNA replication fork, therefore transforming SSBs into genotoxic DSBs. This type of DNA lesion would normally induce HR for repairing damaged DNA. However, if HR-defective exist in tumor cells, including BRCA1/2 deficiency or mutation, another less effective and error-prone DSBs repair pathway NHEJ or alt-NHEJ could be utilized, which causing genomic instability, chromosomal fusions/translocations and subsequently inducing cell death. SSBs, single-strand breaks; DSB, double-strand break; BER, base excision repair; alt-NHEJ, alternative nonhomologous end joining; NHEJ, non-homologous end joining; HR, homologous recombination repair.