Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)

Stable Identifier
R-HSA-5358565
Type
Pathway
Species
Homo sapiens
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MSH2:MSH6 (MutSalpha) binds single base mismatches and unpaired loops of 1-2 nucleotides (reviewed in Edelbrock et al. 2013). Human cells contain about 6-fold more MSH2:MSH6 than MSH2:MSH3 (MutSbeta), which mediates repair of larger mismatches, and an imbalance in the ratio can cause a mutator phenotype (Drummond et al. 1997, Marra et al. 1998). The MSH6 subunit is responsible for binding the mismatch, which activates MSH2:MSH6 to exchange ADP for ATP, adopt the conformation to allow movement on the DNA, and interact with downstream effectors PCNA, MLH1:PMS2 and EXO1. The interaction with PCNA initiates excision of the recently replicated strand. MLH1:PMS2 has endonucleolytic activity and makes a nick that is enlarged to a gap of hundreds of nucleotides by EXO1. DNA is polymerized across the gap by DNA polymerase delta and the remaining nick is sealed by DNA ligase I.

Literature References
PubMed ID Title Journal Year
9671718 Mismatch repair deficiency associated with overexpression of the MSH3 gene

Marra, G, Iaccarino, I, Lettieri, T, Roscilli, G, Delmastro, P, Jiricny, J

Proc. Natl. Acad. Sci. U.S.A. 1998
23391514 Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities

Edelbrock, MA, Kaliyaperumal, S, Williams, KJ

Mutat. Res. 2013
9294177 DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair

Drummond, JT, Genschel, J, Wolf, E, Modrich, P

Proc. Natl. Acad. Sci. U.S.A. 1997
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