Oxidative Stress and the DNA Mismatch Repair Pathway

Significance: Living organisms are under constant assault by a combination of environmental and endogenous oxidative DNA damage, inducing the modification of proteins, lipids, and DNA. Failure to resolve these oxidative modifications is associated with genome instability and the development of many disease states. To maintain genomic integrity, oxidative lesions must be precisely targeted and efficiently resolved. For this, cells have evolved an intricate network of DNA repair mechanisms to detect and repair oxidative DNA damage. Recent Advances: Emerging evidence suggests that in addition to the base excision repair and nucleotide excision repair pathways, the DNA mismatch repair (MMR) pathway plays an important role in mediating oxidative DNA damage repair. Studies in lower organisms and mammalian cells have enabled us to further dissect this critical role and elucidate the precise mechanisms of repair. Critical Issues: Identification of synthetic lethal interactions between MMR deficiency and the accumulation of oxidative DNA damage raises the tantalizing prospect that oxidative DNA-damaging agents may be utilized to selectively target MMR-deficient cancers and potentially other tumor types deficient for oxidative DNA repair molecules. Future Directions: In this review, we emphasize the clinical relevance and potential translation of exploiting this oxidative DNA repair mechanism using synthetic lethality studies in MMR-deficient cells, to develop improved treatment strategies that will benefit cancer patients.