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 Mismatch Repair Pathways in Eukaryotes

DNA mismatch repair (MMR) is a process that maintains DNA homeostasis by facilitating post-replication repair, policing homologous recombination events and protecting against genetic exchange between species. Loss of MMR function results in the accumulation of potential mutations, a mutator phenotype, and genetic instability. As a post-synthesis mismatch repair process, MMR increases the fidelity of DNA replication about 1000-fold. It functions when DNA polymerase exonuclease 3’→5’ proof-reading fails to repair base-pair mismatches. MMR-independent pathways that process some types of mismatches in DNA include nucleotide-excision repair (NER), base excision repair (BER) glycosylases, and the flap endonuclease FEN-1.

Eucaryotic DNA mismatch repair (MMR) is initiated when either a mutSalpha (mutSα) dimer, MSH2(MutS homolog 2):MSH3(MutS homolog 3), or a MutSbeta (mutSβ) dimer, MSH2:MSH6(MutS homolog 6), recognizes and binds to mismatched DNA. The MSH2:MSH6 dimer recognizes base-base mismatches, while both mutS dimers can recognize small loop insertions. Binding of these dimers to mismatch DNA triggers ATP-dependent interaction of another heterodimer with the MSH-mismatch DNA complex. The second interacting heterodimer is a mutL homolog composed of either a mutLalpha (mutLα), MLH1(mutL homolog 1):Pms1(post-meiotic segregation increased 1) or a mutLbeta (mutLβ), MLH1:MLH3(mutL homolog 3) heterodimer. The formation of a ternary mutS:mutL:mismatch DNA complex leads to strand discrimination and error removal by an undefined process. MMS involves other factors such as proliferating cell nuclear antigen (PCNA), replication factor C (RF-C), exonuclease 1 (EXO1), and DNA polymerases δ and ε. PCNA may facilitate the search for mismatched DNA by MSH2:MSH6. RF-C, which contains a DNA-dependent ATPase, is reported to load PCNA onto DNA.