Fig. 1

PARP and PARPis. a The structure schematic of PARP molecule. There are six main domains of PARP1 which include three zinc finger-related domains (DNA binding domains), one BRCA1 C-terminus domain (auto-modification domain), one tryptophan-/glycine-/arginine-rich domain (WGR domain), and one catalytic domain. The catalytic domain of PARP1 consists of two subdomains: one helical domain (HD) and one ADP-ribosyltransferase catalytic domain (ART). b Three-dimensional structure of PARP1 molecule. The above structures were presented by PyMOL Molecular Graphics System (PDB ID: 5XST [104]). c The chemistry structural formula of PARPis. d The function of PARP and synthetic lethal interaction between PARP and HR. Once DNA SSB emerges, PARP1 could recognizes and interacts with SSB by its zinc finger-related domains. After PARP1 binding to damaged DNA chains, the auto-inhibitory function of HD is abrogated and the catalytic function of ART is activated. This catalytic activity leads to the generation of PAR chains on a series of target proteins which promotes the recruitment of DNA repair effectors and chromatin remodeling. Then the auto-PARylation on PARP1 protein causes the dissociation of PARP1 from DNA chains and restores the auto-inhibitory status of PARP1. For HR deficient tumor cells, active SSB repair pathways is the vital prerequisites for cell survival. After PARPi treatment, NHEJ is used to repair PARPi-introduced DSB. However, NHEJ is a rapid as well as error-prone repair pathway by direct ligation. Due to the low-fidelity, NHEJ often produces plenty of chromosomal rearrangements and these unsustainable DNA damages are harmful to cell viability