New insights into the mechanism of DNA mismatch repair

Abstract

The genome of all organisms is constantly being challenged by endogenous and exogenous sources of DNA damage. Errors like base:base mismatches or small insertions and deletions, primarily introduced by DNA polymerases during DNA replication are repaired by an evolutionary conserved DNA mismatch repair (MMR) system. The MMR system, together with the DNA replication machinery, promote repair by an excision and resynthesis mechanism during or after DNA replication, increasing replication fidelity by upto-three orders of magnitude. Consequently, inactivation of MMR genes results in elevated mutation rates that can lead to increased cancer susceptibility in humans. In this review, we summarize our current understanding of MMR with a focus on the different MMR protein complexes, their function and structure. We also discuss how recent findings have provided new insights in the spatio-temporal regulation and mechanism of MMR.

DNA mismatch repair and the DNA damage response

“…Recent studies in Saccharomyces cerevisiae point to both EXO1-dependent and -independent excision pathways, the latter being dependent on the PMS1 (mammalian PMS2) endonuclease activity (discussed in [84]). Paradoxically, although EXO1 is the only exonuclease known to participate in the excision step of MMR and is required for in vitro MMR reactions, inactivation of EXO1 in S. cerevisiae confers only a mild mutator phenotype and, in mice, fails to fully recapitulate either the mutational or tumor spectrum observed in animals missing essential MMR proteins (see [2,84]). The notion that EXO1 plays distinct structural and catalytic roles in MMR derives from experiments in S .…”

“…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.…”

Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis

“…DNA replication fidelity | mismatch repair | CTP biosynthesis | DNA polymerases | dNTP pool imbalance T he fidelity of DNA replication is strongly influenced by three processes (1-3): (i) nucleotide selectivity, wherein replicative DNA polymerases select the correct dNTP to be incorporated; (ii) DNA polymerase proofreading activity, which excises wrongly incorporated nucleotides by using the DNA polymerase 3′-to-5′ exonuclease activity; and (iii) mismatch repair (MMR) (4,5), a DNA replication-coupled repair mechanism (6, 7), which corrects errors that escaped proofreading. Furthermore, the balance and overall concentration of dNTPs not only affect nucleotide selection but also influence DNA polymerase proofreading activity (8).…”

A personal historical view of DNA mismatch repair with an emphasis on eukaryotic DNA mismatch repair

“…However, in places where it was important to specifically refer to a human or mouse gene/protein, I have included the suffixes sc ( S. cerevisiae ), h (human) and mus (mouse) to help prevent confusion. A useful summary table of MMR genes, proteins and protein complexes has been published recently [17] (see the minireview by Putnam in this issue).…”