DNA repair in cancer: emerging targets for personalized therapy

Abstract

Genomic deoxyribonucleic acid (DNA) is under constant threat from endogenous and exogenous DNA damaging agents. Mammalian cells have evolved highly conserved DNA repair machinery to process DNA damage and maintain genomic integrity. Impaired DNA repair is a major driver for carcinogenesis and could promote aggressive cancer biology. Interestingly, in established tumors, DNA repair activity is required to counteract oxidative DNA damage that is prevalent in the tumor microenvironment. Emerging clinical data provide compelling evidence that overexpression of DNA repair factors may have prognostic and predictive significance in patients. More recently, DNA repair inhibition has emerged as a promising target for anticancer therapy. Synthetic lethality exploits intergene relationships where the loss of function of either of two related genes is nonlethal, but loss of both causes cell death. Exploiting this approach by targeting DNA repair has emerged as a promising strategy for personalized cancer therapy. In the current review, we focus on recent advances with a particular focus on synthetic lethality targeting in cancer.

Keywords: biomarker; drug target; synthetic lethality.

Figure 1

Types of DNA damage and DNA repair pathways. Abbreviation: DNA, deoxyribonucleic acid.

Figure 2

Synthetic lethality in BRCA^−/− cells upon PARP inhibition. PARP inhibition leads to SSBs. During replication SSBs get converted to DSBs. BRCA^−/− cells are deficient in HR and hence unable to repair DSBs. DSB accumulation leads to cell death. In cells where PARP is proficient, SSBs are repaired by BER irrespective of BRCA status. There is no DSB generation, and cells continue to survive. Abbreviations: BER, base excision repair; BRCA, breast cancer susceptibility protein; DSB, double-strand break; HR, homologous recombination; PARP, poly[ADP-ribose] polymerase 1; SSB, single-strand break.