Widening the BRCAness therapeutic window for its synthetic lethality effects with PARP inhibitors

This review examines the expanding role of PARP inhibitors in cancer therapy, moving beyond the traditional model of single-strand break repair inhibition and BRCA-dependent synthetic lethality. We highlight emerging evidence that PARP inhibitors induce cytotoxicity through replication-associated DNA damage, including defects in Okazaki fragment maturation and replication gap accumulation. By integrating recent mechanistic insights with findings from CRISPR-based screens, we outline how disruptions in DNA replication and repair pathways define a broader BRCAness phenotype. We further emphasize the clinical implications of these discoveries, including novel combination strategies that extend the therapeutic applicability of PARP inhibitors beyond prevailing treatment regimens. The intersection of PARP enzymes and Okazaki Fragment Maturation is analyzed, emphasizing the multiple pathways implicated in sensitivity to PARP inhibition, with implications for development of novel therapeutic opportunities for PARP inhibitors.