Reactome | MSH2:MSH6 recruits MLH1:PMS2 to mismatch and interacts with PCNA

MSH2:MSH6 recruits MLH1:PMS2 to mismatch and interacts with PCNA

Stable Identifier

R-HSA-5358510

Type

Reaction [binding]

Species

Homo sapiens

Compartment

nucleoplasm

Synonyms

MutSalpha binds ATP and recruits MutLalpha to mismatch

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MSH2:MSH6 recruits MLH1:PMS2 to mismatch and interacts with PCNA

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After being activated by a mismatch, MSH2:MSH6 (MutSalpha) recruits MLH1:PMS2 (MutLalpha) to form a ternary complex with mismatched DNA (Gu et al. 1998, Blackwell et al. 2001, Plotz et al. 2002). As inferred from yeast, multiple MLH1:PMS2 complexes may be loaded at each mismatch (Hombauer et al. 2011). MSH2:MSH6 and MLH1:PMS2 interact with PCNA (Gu et al. 1998, Clark et al. 2000, Kleczkowska et al. 2001, Zhang et al. 2005, Constantin et al. 2005, Iyer et al. 2008, Masih et al. 2008, Iyer et al. 2010). The binding sites for MLH1:PMS2 and PCNA are distinct on MSH2:MSH6 so it is possible that both can bind simultaneously (Iyer et al. 2010). The interaction with PCNA appears to direct the orientation of the repair complex so as to determine which strand will be used as template and which strand will be repaired. In vivo, the recently replicated strand is repaired. In vitro, the strand containing a nick is repaired (Zhang et al. 2005, Constantin et al. 2005), possibly due to the ability of the nick to orient the loading of PCNA onto DNA by RFC (Pluciennik et al. 2010).

Literature References

PubMed ID	Title	Journal	Year
11809883	hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA Plotz, G, Raedle, J, Brieger, A, Trojan, J, Zeuzem, S	Nucleic Acids Res.	2002
11274057	hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci Kleczkowska, HE, Marra, G, Lettieri, T, Jiricny, J	Genes Dev.	2001
16143102	Reconstitution of 5'-directed human mismatch repair in a purified system Zhang, Y, Yuan, F, Presnell, SR, Tian, K, Gao, Y, Tomkinson, AE, Gu, L, Li, GM	Cell	2005
20713735	PCNA function in the activation and strand direction of MutL? endonuclease in mismatch repair Pluciennik, A, Dzantiev, L, Iyer, RR, Constantin, N, Kadyrov, FA, Modrich, P	Proc. Natl. Acad. Sci. U.S.A.	2010
11441019	DNA chain length dependence of formation and dynamics of hMutSalpha.hMutLalpha.heteroduplex complexes Blackwell, LJ, Wang, S, Modrich, P	J. Biol. Chem.	2001
11005803	Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes Clark, AB, Valle, F, Drotschmann, K, Gary, RK, Kunkel, TA	J. Biol. Chem.	2000
16188885	Human mismatch repair: reconstitution of a nick-directed bidirectional reaction Constantin, N, Dzantiev, L, Kadyrov, FA, Modrich, P	J. Biol. Chem.	2005
20154325	MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta Iyer, RR, Pluciennik, A, Genschel, J, Tsai, MS, Beese, LS, Modrich, P	J. Biol. Chem.	2010
22118461	Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates Hombauer, H, Campbell, CS, Smith, CE, Desai, A, Kolodner, RD	Cell	2011
18326858	The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair Iyer, RR, Pohlhaus, TJ, Chen, S, Hura, GL, Dzantiev, L, Beese, LS, Modrich, P	J. Biol. Chem.	2008
17984070	Mismatch Repair proteins are recruited to replicating DNA through interaction with Proliferating Cell Nuclear Antigen (PCNA) Masih, PJ, Kunnev, D, Melendy, T	Nucleic Acids Res.	2008