DNA mismatch repair and oxidative DNA damage: implications for cancer biology and treatment

Abstract

Many components of the cell, including lipids, proteins and both nuclear and mitochondrial DNA, are vulnerable to deleterious modifications caused by reactive oxygen species. If not repaired, oxidative DNA damage can lead to disease-causing mutations, such as in cancer. Base excision repair and nucleotide excision repair are the two DNA repair pathways believed to orchestrate the removal of oxidative lesions. However, recent findings suggest that the mismatch repair pathway may also be important for the response to oxidative DNA damage. This is particularly relevant in cancer where mismatch repair genes are frequently mutated or epigenetically silenced. In this review we explore how the regulation of oxidative DNA damage by mismatch repair proteins may impact on carcinogenesis. We discuss recent studies that identify potential new treatments for mismatch repair deficient tumours, which exploit this non-canonical role of mismatch repair using synthetic lethal targeting.

Figure 1

Repair of oxidative DNA lesions by the MMR pathway. Schematic representation of the hypothesised mechanisms of oxidative damage removal by MMR. ROS can induce lesions in the DNA, such as oxidation of guanine to 8-oxoG. These are recognised by MutSα which recruits MutL. The sliding clamp model of MMR proposes that the ternary MutSα/MutL complex moves along the DNA until it encounters RFC and PCNA bound to the 5' end of the daughter strand. RFC is consequently displaced which allows the recruitment EXO1 that mediates the degradation of the region containing the oxidative lesion. The resulting single-stranded gap is stabilised by the presence of RPA. Once the oxidative lesion is removed, EXO1 activity is no longer promoted by MutSα and is actually inhibited by MutL. A DNA polymerase (DNA Pol) synthesises new DNA to fill the gap and this is connected to the daughter strand by LIG1. The BER DNA glycosylase MUTYH has been shown to bind to MutSα via MSH6 whilst MutSα enhances the removal of 8-oxoG/A mismatched lesions by MUTYH. Tandem lesions of 8-oxoG and 5-hydroxyuracil within OCDLs may be recognised by MutSα, leading to the recruitment of EXO1 and removal of all or part of the lesion. PCNA is then loaded onto the resulting 3'OH ssDNA gap, possibly due to a direct interaction with MutSα. Rad6/Rad18 mediates the monoubiquitination of PCNA and MutSα is required for this process. Monoubiquitinated PCNA recruits DNA Polη, which synthesises new DNA across the damaged or undamaged template.

Figure 2

Accumulation of oxidative DNA damage causes synthetic lethality in MSH2 and MLH1 deficient cells. Silencing of POLB, POLG and PINK1 or treatment of cells with the chemotherapeutic drug, methotrexate causes 8-oxoG lesions in DNA which can be successfully repaired in MMR competent cells. However, in MSH2 (A) or MLH1 (B) deficient cells 8-oxoG lesions accumulate in the nuclear (A) and mitochondrial (B) DNA respectively, leading to cell death.