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

Stable Identifier
Reaction [binding]
Homo sapiens
MutSalpha binds ATP and recruits MutLalpha to mismatch
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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
11274057 hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci

Jiricny, J, Marra, G, Lettieri, T, Kleczkowska, HE

Genes Dev. 2001
11809883 hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA

Raedle, J, Zeuzem, S, Brieger, A, Trojan, J, Plotz, G

Nucleic Acids Res. 2002
16143102 Reconstitution of 5'-directed human mismatch repair in a purified system

Gao, Y, Zhang, Y, Li, GM, Yuan, F, Tian, K, Presnell, SR, Gu, L, Tomkinson, AE

Cell 2005
20713735 PCNA function in the activation and strand direction of MutL? endonuclease in mismatch repair

Dzantiev, L, Modrich, P, Iyer, RR, Kadyrov, FA, Pluciennik, A, Constantin, N

Proc. Natl. Acad. Sci. U.S.A. 2010
11441019 DNA chain length dependence of formation and dynamics of hMutSalpha.hMutLalpha.heteroduplex complexes

Wang, S, Blackwell, LJ, Modrich, P

J. Biol. Chem. 2001
11005803 Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes

Drotschmann, K, Clark, AB, Kunkel, TA, Gary, RK, Valle, F

J. Biol. Chem. 2000
16188885 Human mismatch repair: reconstitution of a nick-directed bidirectional reaction

Dzantiev, L, Modrich, P, Kadyrov, FA, Constantin, N

J. Biol. Chem. 2005
20154325 MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta

Tsai, MS, Modrich, P, Beese, LS, Iyer, RR, Pluciennik, A, Genschel, J

J. Biol. Chem. 2010
22118461 Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates

Desai, A, Hombauer, H, Kolodner, RD, Smith, CE, Campbell, CS

Cell 2011
18326858 The MutSalpha-proliferating cell nuclear antigen interaction in human DNA mismatch repair

Dzantiev, L, Pohlhaus, TJ, Modrich, P, Beese, LS, Hura, GL, Iyer, RR, Chen, S

J. Biol. Chem. 2008
17984070 Mismatch Repair proteins are recruited to replicating DNA through interaction with Proliferating Cell Nuclear Antigen (PCNA)

Kunnev, D, Masih, PJ, Melendy, T

Nucleic Acids Res. 2008
Orthologous Events
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