DNA mismatch repair and the DNA damage response

Abstract

This review discusses the role of DNA mismatch repair (MMR) in the DNA damage response (DDR) that triggers cell cycle arrest and, in some cases, apoptosis. Although the focus is on findings from mammalian cells, much has been learned from studies in other organisms including bacteria and yeast [1,2]. MMR promotes a DDR mediated by a key signaling kinase, ATM and Rad3-related (ATR), in response to various types of DNA damage including some encountered in widely used chemotherapy regimes. An introduction to the DDR mediated by ATR reveals its immense complexity and highlights the many biological and mechanistic questions that remain. Recent findings and future directions are highlighted.

Mismatch binding, ADP–ATP exchange and intramolecular signaling during mismatch repair

“…Some of these promote genome stability, such as suppression of homeologous recombination (by disrupting exchange between heteroduplex DNA substrates) [12,92], while others promote genome instability, such as expansion of triplet nucleotide repeat (TNR) sequences [93], processing of DNA oxidative damage lesions [94], and somatic hypermutation for antibody diversity [95]. For example, Msh2-Msh3 (MutSβ), which binds and initiates repair of insertion/deletion loops (post-replication or during recombination), also binds double strand/single strand junctions (for removal of 3’non-homologous tails in double strand break repair) [96], as well as secondary structures formed by repeat sequences (leading to TNR expansion and related neurological disorders) [97].…”

Mouse models of DNA mismatch repair in cancer research

“…Exposure to TMZ causes the formation of O 6 -methylguanine lesions that if left unrepaired can cause the formation of aberrant base pairs upon replication. These aberrant base pairs are subsequently recognized by MMR complexes, which mediate cell cycle arrest and apoptosis [52,53] this issue. In MMR-deficient cells, this genotoxic response is impaired resulting in the survival of MMR-deficient cells that also display increased mutation rates.…”

Non-canonical actions of mismatch repair

“…With high levels of DNA damage, it has been shown in numerous experiments that MMR plays an important role in damage signaling and apoptosis; see Li et al in this special issue and other references [1–5, 16, 69, 72, 74–76]. …”

“…The particular importance of MMR in damage signaling is illustrated by the very large increase in cell survival to high doses of MNNG in cells lacking functional MMR [1–5, 72, 75, 76]. The current status of damage signaling and MMR is reviewed in this issue by Li et al [16]. …”

“…My lab for example recently demonstrated, in an assay system in yeast specific for base pair mutations, that loss of MMR resulted in a relatively small increase in base pair substitutions [13] but was extremely important in the absence of proofreading [14]. It has been known for many years that MMR could recognize mispairs containing damaged bases [3–6, 15, 16], and we suggested that MMR has a much more important role in suppressing mutations due to damaged bases than for mispairs containing only undamaged bases [13, 17]. In addition to damaged bases, it has also been shown that MMR can target mispairs involving ribonucleotides [18].…”