PARP1 roles in DNA repair and DNA replication: The basi(c)s of PARP inhibitor efficacy and resistance

Genome integrity is the subject of constant insult from endogenous and exogenous sources. In order to cope, eukaryotic cells have evolved an elaborate network of DNA repair factors that accommodate diverse lesion types and exhibit considerable functional redundancy. PARP1 is a major sensor of DNA breaks with established and putative roles in a number of pathways within the DNA repair network, including single- and double-strand break repair as well as DNA replication fork protection. Importantly, PARP1 is the major target of small-molecule PARP inhibitors (PARPi), which are employed in the treatment of homologous recombination (HR)-deficient tumors, as the latter are particularly susceptible to the accumulation of DNA damage due to an inability to efficiently repair highly toxic double-strand DNA breaks. The clinical success of PARPi has fostered extensive research into PARP biology, which has shed light on the involvement of PARP1 in various genomic transactions. A major goal within the field has been to understand the relationship between catalytic inhibition and PARP1 trapping. The specific consequences of inhibition and trapping on genomic stability as a basis for PARPi cytotoxicity remain a matter of debate. Finally, PARP inhibition is increasingly recognized for its capacity to elicit/modulate antitumor immunity. The clinical potential of PARPi is, however, hindered by the development of resistance. Hence, extensive efforts are invested in identifying factors that promote resistance or sensitize cells to PARPi. The current review provides a summary of advances in our understanding of PARP1 biology, the mechanistic nature and molecular consequences of PARP inhibition, as well as the mechanisms that give rise to PARPi resistance. © 2023 The Author(s)