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

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

Stable Identifier

R-HSA-5358565

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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

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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
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
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
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