Özet:

Human cells are equipped with a complex DNA damage response mechanism to deal with endogenously or exogenously induced genome damages. In the case of impaired DNA damage response functionality, cells start accumulating various DNA lesions which, if not repaired, threat genome stability. Although inefficient DNA damage response activity can promote neoplastic transformation, anti-cancer treatment resistance and serious side effects, any specific DDR dysfunctionality could serve as a biomarker to predict therapeutic response or a pharmacologic target to render cancer cells more vulnerable to chemotherapeutics. Poly (ADP-ribose) (PARP) enzymes participate in various cellular processes, including DNA single-strand break repair pathway. BRCA1/2 proteins play essential roles in homologous recombination DNA double-strand break repair pathway. Recent studies showed that cells with homologous recombination deficiency due to BRCA1/2 mutations become sensitive to PARP inhibitors. The successful clinical implementation of the synthetic lethal interaction between BRCA1/2 and PARP has motivated researchers to investigate other possible biomarkers to evaluate homologous recombination efficiency and untangle other potential synthetic lethal interactions to overcome PARP inhibitor resistance. In this review, we first summarize the current understanding of DNA damage response activated upon DNA double-strand break formation, then explain the synthetic lethality between homologous recombination-mediated repair and PARP inhibition.

Anahtar Kelimeler: