Mismatch Repair (Homo sapiens)

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10, 19, 22, 26, 36...8, 21, 27, 29, 34...23, 33, 38, 39, 41...11, 15, 21, 28, 35...17, 21, 23, 38, 4620, 21, 24, 38, 6017, 21, 23, 38, 4621, 25, 33, 38, 39, 41...1, 5, 7, 12, 40...1, 3, 6, 13, 16...20, 30, 42, 5813, 381, 5, 7, 9, 14...24, 382, 4, 20, 21, 30...cytoplasmnucleoplasmATPdCTPRPA heterotrimerdGTPMSH2:MSH3:ADPRPA heterotrimerdATPDNA containingsingle strand nick(5' phosphate, 3'hydroxyl)PPiADPMSH2:MSH3:ATP:DNAcontaining IDL of 2bases or moredTTPMSH2:MSH6:ATP:DNAcontaining 1-2 basemismatchATPMSH2:MSH6:ADPDNA containingmismatch or 1-2base IDLMLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionAMPPCNA homotrimerDNA Polymerase deltatetramerMSH2:MSH3:ADP:DNAcontaining IDL of 2bases or moreMSH2:MSH6:ADP:DNAcontaining 1-2 basemismatchMLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatchEXO1RPA:DNA containingsingle strand gapEXO1:MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionRepaireddouble-stranded DNAATPEXO1:MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionADPMLH1:PMS2MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 bases or moreDNA containing IDLof 2 or more basesMLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionLIG17, 535324242


Description

The mismatch repair (MMR) system corrects single base mismatches and small insertion and deletion loops (IDLs) of unpaired bases. MMR is primarily associated with DNA replication and is highly conserved across prokaryotes and eukaryotes. MMR consists of the following basic steps: a sensor (MutS homologue) detects a mismatch or IDL, the sensor activates a set of proteins (a MutL homologue and an exonuclease) that select the nascent DNA strand to be repaired, nick the strand, exonucleolytically remove a region of nucleotides containing the mismatch, and finally a DNA polymerase resynthesizes the strand and a ligase seals the remaining nick (reviewed in Kolodner and Marsischkny 1999, Iyer et al. 2006, Li 2008, Fukui 2010, Jiricny 2013).
Humans have 2 different MutS complexes. The MSH2:MSH6 heterodimer (MutSalpha) recognizes single base mismatches and small loops of one or two unpaired bases. The MSH2:MSH3 heterodimer (MutSbeta) recognizes loops of two or more unpaired bases. Upon binding a mismatch, the MutS complex becomes activated in an ATP-dependent manner allowing for subsequent downstream interactions and movement on the DNA substrate. (There are two mechanisms proposed: a sliding clamp and a switch diffusion model.) Though the order of steps and structural details are not fully known, the activated MutS complex interacts with MLH1:PMS2 (MutLalpha) and PCNA, the sliding clamp present at replication foci. The role of PCNA is multifaceted as it may act as a processivity factor in recruiting MMR proteins to replicating DNA, interact with MLH1:PMS2 and Exonuclease 1 (EXO1) to initiate excision of the recently replicated strand and direct DNA polymerase delta to initiate replacement of bases. MLH1:PMS2 makes an incision in the strand to be repaired and EXO1 extends the incision to make a single-stranded gap of up to 1 kb that removes the mismatched base(s). (Based on assays of purified human proteins, there is also a variant of the mismatch repair pathway that does not require EXO1, however the mechanism is not clear. EXO1 is almost always required, it is possible that the exonuclease activity of DNA polymerase delta may compensate in some situations and it has been proposed that other endonucleases may perform redundant functions in the absence of EXO1.) RPA binds the single-stranded region and a new strand is synthesized across the gap by DNA polymerase delta. The remaining nick is sealed by DNA ligase I (LIG1).
Concentrations of MMR proteins MSH2:MSH6 and MLH1:PMS2 increase in human cells during S phase and are at their highest level and activity during this phase of the cell cycle (Edelbrock et al. 2009). Defects in MSH2, MSH6, MLH1, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) (reviewed in Martin-Lopez and Fishel 2013). View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114878view16:38, 25 January 2021ReactomeTeamReactome version 75
113324view11:39, 2 November 2020ReactomeTeamReactome version 74
112535view15:49, 9 October 2020ReactomeTeamReactome version 73
101448view11:32, 1 November 2018ReactomeTeamreactome version 66
100986view21:10, 31 October 2018ReactomeTeamreactome version 65
100522view19:44, 31 October 2018ReactomeTeamreactome version 64
100069view16:28, 31 October 2018ReactomeTeamreactome version 63
99620view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93791view13:36, 16 August 2017ReactomeTeamreactome version 61
93325view11:20, 9 August 2017ReactomeTeamreactome version 61
87945view13:05, 25 July 2016RyanmillerOntology Term : 'DNA repair pathway' added !
87940view13:04, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86412view09:17, 11 July 2016ReactomeTeamreactome version 56
83379view11:04, 18 November 2015ReactomeTeamVersion54
81555view13:05, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
DNA Polymerase delta tetramerR-HSA-68450 (Reactome)
DNA containing

mismatch or 1-2

base IDL		R-NUL-5358514 (Reactome)
DNA containing

single strand nick (5' phosphate, 3'

hydroxyl)		R-NUL-5358610 (Reactome)
DNA containing IDL of 2 or more basesR-NUL-5358527 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionR-HSA-5358541 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionR-HSA-5358633 (Reactome)
EXO1ProteinQ9UQ84 (Uniprot-TrEMBL)
LIG1ProteinP18858 (Uniprot-TrEMBL)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 bases or moreR-HSA-5358523 (Reactome)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionR-HSA-5358515 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionR-HSA-5358528 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatchR-HSA-5358511 (Reactome)
MLH1:PMS2R-HSA-5357522 (Reactome)
MSH2:MSH3:ADP:DNA

containing IDL of 2

bases or more		R-HSA-5358532 (Reactome)
MSH2:MSH3:ADPR-HSA-5357508 (Reactome)
MSH2:MSH3:ATP:DNA

containing IDL of 2

bases or more		R-HSA-5358910 (Reactome)
MSH2:MSH6:ADP:DNA

containing 1-2 base

mismatch		R-HSA-5358524 (Reactome)
MSH2:MSH6:ADPR-HSA-5357523 (Reactome)
MSH2:MSH6:ATP:DNA

containing 1-2 base

mismatch		R-HSA-5358934 (Reactome)
PCNA homotrimerR-HSA-68440 (Reactome)
PPiMetaboliteCHEBI:29888 (ChEBI)
RPA heterotrimerR-HSA-68462 (Reactome)
RPA:DNA containing single strand gapR-HSA-5358538 (Reactome)
Repaired double-stranded DNAR-NUL-109966 (Reactome)
dATPMetaboliteCHEBI:16284 (ChEBI)
dCTPMetaboliteCHEBI:16311 (ChEBI)
dGTPMetaboliteCHEBI:16497 (ChEBI)
dTTPMetaboliteCHEBI:18077 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5358912 (Reactome)
ADPArrowR-HSA-5358919 (Reactome)
AMPArrowR-HSA-5358592 (Reactome)
ATPR-HSA-5358592 (Reactome)
ATPR-HSA-5358912 (Reactome)
ATPR-HSA-5358919 (Reactome)
DNA Polymerase delta tetramermim-catalysisR-HSA-5358579 (Reactome)
DNA containing

mismatch or 1-2

base IDL		R-HSA-5358525 (Reactome)
DNA containing

single strand nick (5' phosphate, 3'

hydroxyl)		ArrowR-HSA-5358579 (Reactome)
DNA containing

single strand nick (5' phosphate, 3'

hydroxyl)		R-HSA-5358592 (Reactome)
DNA containing IDL of 2 or more basesR-HSA-5358513 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionArrowR-HSA-5358545 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionR-HSA-5358619 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionmim-catalysisR-HSA-5358619 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionArrowR-HSA-5358597 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionR-HSA-5358599 (Reactome)
EXO1:MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionmim-catalysisR-HSA-5358599 (Reactome)
EXO1R-HSA-5358545 (Reactome)
EXO1R-HSA-5358597 (Reactome)
LIG1mim-catalysisR-HSA-5358592 (Reactome)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 bases or moreArrowR-HSA-5358519 (Reactome)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 bases or moreR-HSA-5358512 (Reactome)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 bases or moremim-catalysisR-HSA-5358512 (Reactome)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionArrowR-HSA-5358512 (Reactome)
MLH1:PMS2:MSH2:MSH3:ATP:PCNA:DNA containing IDL of 2 or more bases and single strand incisionR-HSA-5358545 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionArrowR-HSA-5358518 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatch and single strand incisionR-HSA-5358597 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatchArrowR-HSA-5358510 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatchR-HSA-5358518 (Reactome)
MLH1:PMS2:MSH2:MSH6:ATP:PCNA:DNA containing 1-2 base mismatchmim-catalysisR-HSA-5358518 (Reactome)
MLH1:PMS2R-HSA-5358510 (Reactome)
MLH1:PMS2R-HSA-5358519 (Reactome)
MSH2:MSH3:ADP:DNA

containing IDL of 2

bases or more		ArrowR-HSA-5358513 (Reactome)
MSH2:MSH3:ADP:DNA

containing IDL of 2

bases or more		R-HSA-5358919 (Reactome)
MSH2:MSH3:ADPR-HSA-5358513 (Reactome)
MSH2:MSH3:ATP:DNA

containing IDL of 2

bases or more		ArrowR-HSA-5358919 (Reactome)
MSH2:MSH3:ATP:DNA

containing IDL of 2

bases or more		R-HSA-5358519 (Reactome)
MSH2:MSH6:ADP:DNA

containing 1-2 base

mismatch		ArrowR-HSA-5358525 (Reactome)
MSH2:MSH6:ADP:DNA

containing 1-2 base

mismatch		R-HSA-5358912 (Reactome)
MSH2:MSH6:ADPR-HSA-5358525 (Reactome)
MSH2:MSH6:ATP:DNA

containing 1-2 base

mismatch		ArrowR-HSA-5358912 (Reactome)
MSH2:MSH6:ATP:DNA

containing 1-2 base

mismatch		R-HSA-5358510 (Reactome)
PCNA homotrimerR-HSA-5358510 (Reactome)
PCNA homotrimerR-HSA-5358519 (Reactome)
PPiArrowR-HSA-5358592 (Reactome)
R-HSA-5358510 (Reactome) 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).
R-HSA-5358512 (Reactome) The latent endonuclease activity of MLH1:PMS2 (MutLalpha) is activated by interaction with MSH2:MSH3 (MutSbeta) (Zhang et al. 2005, and inferred from activation of MLH1:PMS2 by MSH2:MSH6). MLH1:PMS2 makes a nick in the strand of DNA that will be repaired (Kadyrov et al. 2006).
R-HSA-5358513 (Reactome) MSH2:MSH3 (MutSbeta) binds preferentially to insertions and deletion loops (IDLs) of 2 bases or more (Palombo et al. 1996, Drummond et al. 1997, Genschel et al. 1998, Tian et al. 2009, Panigrahi et al. 2010, Kantelinen et al. 2010, Gupta et al. 2012). Unlike MSH2:MSH6 (MutSalpha), which binds the base of a mismatched nucleotide, MSH2:MSH3 binds 3 phosphates in the loop of unpaired nucleotides (Gupta et al. 2012). MSH2:MSH3 is localized at replication foci during S phase via an interaction between MSH3 and PCNA (Kleczkowska et al. 2001).
R-HSA-5358518 (Reactome) The latent endonuclease activity of MLH1:PMS2 (MutLalpha) is activated by interaction with MSH2:MSH6 and PCNA (Kadyrov et al 2006). MLH1:PMS2 makes a nick in the replicated strand of DNA. As inferred from yeast, more than one MLH1:PMS2 may bind per MSH2:MSH6 (Hombauer et al. 2011). Strand selection of the nick is determined by interaction with PCNA, though the exact mechanism is unknown (Pluciennik et al 2010).
R-HSA-5358519 (Reactome) After being activated by an insertion/deletion loop (IDL), MSH2:MSH3 (MutSbeta) recruits MLH1:PMS2 (MutLalpha) (Iyer et al. 2010, Pluciennik et al. 2013) and interacts with PCNA (Iyer et al. 2010). As inferred from yeast, more than one molecule of MLH1:PMS2 may bind per molecule of MSH2:MSH3 (Hombauer et al. 2011). MLH1:PMS2 and PCNA compete for the same binding site on MSH2:MSH3 (Iyer et al. 2010). The interaction with PCNA determines which strand of DNA will serve as template and which strand will be repaired (Zhang et al. 2005, and inferred from MSH2:MSH6).
R-HSA-5358525 (Reactome) The MSH2:MSH6 (MutSalpha) heterodimer binds single base mismatches and insertion or deletion loops (IDLs) of 1-2 bases (Drummond et al. 1997, Genschel et al. 1998, Gradia et al. 2000, Zhang et al. 2005, Constantin et al. 2005, Tian et al. 2009, reviewed in Edelbrock et al. 2013). The MSH6 subunit contains a Phe-X-Glu motif that binds the mismatched base (Dufner et al 2000, Warren et al. 2007). During replication most nuclear MSH2:MSH6 is observed to colocalize with PCNA via an interaction between PCNA and MSH6 at replication forks during S phase (Kleczkowska et al. 2001), presumably coupling mismatch repair to DNA replication. The MSH6 subunit of MSH2:MSH6 also binds histone H3 methylated at lysine-36, which is enriched in chromatin during G1 and early S phase (Li et al. 2013).
R-HSA-5358545 (Reactome) EXO1 interacts with MSH2 and MLH1 (and therefore is presumed to interact with their respective heterodimers MSH2:MSH3 and MLH1:PMS2), forming a ternary complex with MLH1:PMS2 (Nielsen et al. 2004). EXO1 also interacts with PCNA in S phase (Nielsen et al. 2004, Zhang et al. 2005, Constantin et al. 2005, Knudsen et al. 2007, Liberti et al. 2011)
R-HSA-5358579 (Reactome) DNA polymerase delta synthesizes DNA across a single-stranded gap during mismatch repair (Longley et al. 1997, Zhang et al. 2005, Constantin et al. 2005, reviewed in Prindle and Loeb 2012). RPA stimulates the activity of DNA polymerase delta (Dong et al. 1999). DNA polymerase delta does not displace strands during synthesis (Randahl et al. 1988).
R-HSA-5358592 (Reactome) LIG1 (DNA ligase I) catalyzes the formation of a phosphodiester bond between a 3' hydroxyl group and a 5' phosphate group to form an intact DNA strand (Bhat and Grossman 1986). ATP is hydrolyzed to AMP and pyrophosphate in a reaction mechanism that involves adenylylation of a lysine residue of the enzyme, transfer of the adenylyl group to the 5' phosphate of DNA, and nick sealing by nucleophilic attack of the 3' hydroxyl group on the adenylylated 5' phosphate (Taylor et al. 2011, reviewed in Tomkinson et al. 2006). RPA stimulates the activity of LIG1 about 15-fold (Ranalli et al. 2002). LIG1 is recruited to repair sites by interaction with PCNA (Mortusewicz et al. 2006). Ligation is the final step in mismatch repair (Zhang et al. 2005, Constantin et al. 2005).
R-HSA-5358597 (Reactome) EXO1 interacts with MSH2 and MLH1 (and therefore is presumed to interact with their respective heterodimers MSH2:MSH6 and MLH1:PMS2), forming a ternary complex with MLH1:PMS2 (Nielsen et al. 2004). EXO1 also interacts with PCNA in S phase (Nielsen et al. 2004, Zhang et al. 2005, Constantin et al. 2005, Knudsen et al. 2007, Liberti et al. 2011)
R-HSA-5358599 (Reactome) EXO1 exonucleolytically degrades the strand being repaired in a 5' to 3' direction (Genschel et al. 2002, Genschel and Modrich 2003, Dzantiev et al. 2004, Zhang et al. 2005, Constantin et al. 2005, Genschel and Modrich 2006, Orans et al. 2011) to create a single -stranded gap extending 90-170 nucleotides beyond the mismatch (Fang and Modrich 1993). Interaction of MSH2:MSH6 (MutSalpha) with EXO1 reduces the exonuclease activity of EXO1 on correctly paired DNA duplexes (Orans et al. 2011). MLH1:PMS2 limits the length of excisions by EXO1 (Zhang et al. 2005). EXO1 also forms a complex with PCNA during S phase (Liberti et al. 2011). RPA binds the resulting single-stranded DNA (Lin et al. 1998, Ramilo et al. 2002, Zhang et al. 2005, reviewed in Iftode et al. 1999).
R-HSA-5358619 (Reactome) EXO1 exonucleolytically degrades the strand being repaired in a 5' to 3' direction (Zhang et al. 2005, Orans et al. 2011, and inferred from EXO1 activity with MSH2:MSH6) to create a single -stranded gap extending 90-170 nucleotides beyond the insertion/deletion loop (IDL) (Fang and Modrich 1993). MLH1:PMS2 limits the length of excisions by EXO1 (Zhang et al. 2005). EXO1 also forms a complex with PCNA during S phase (Liberti et al. 2011). RPA binds the resulting single-stranded DNA (Lin et al. 1998, Ramilo et al. 2002, Zhang et al. 2005, reviewed in Iftode et al. 1999).
R-HSA-5358912 (Reactome) After binding a mismatch, the MSH2:MSH6 (MutSalpha) heterodimer exchanges ADP for ATP, which alters its conformation to a sliding clamp or molecular switch able to diffuse in one direction along duplex DNA (Gradia et al. 1997, Blackwell et al. 1998, Gradia et al. 1999, Gradia et al. 2000). Each heterodimer can bind 2 molecules of ATP or ADP or a combination of ADP and ATP. The affinities and hydrolysis rates of the binding sites differ (Tian et al. 2009, Heinen et al. 2011). However, the exact location of a given adenosine at a given binding location and the conferred function is unclear but believed to control downstream events. Hydrolysis of the ATP by MSH2:MSH6 is not required for mismatch binding but is required for subsequent mismatch repair (Gu et al. 1998, Tian et al. 2009, Geng et al. 2012).
R-HSA-5358919 (Reactome) After binding a mismatch, the MSH2:MSH3 (MutSbeta) heterodimer exchanges ADP for ATP, which changes the conformation of MSH2:MSH3 to a sliding clamp or molecular switch able to diffuse in one direction along duplex DNA (Gu et al. 1998, Zhang et al. 2005, and inferred from MSH2:MSH6).
RPA heterotrimerArrowR-HSA-5358579 (Reactome)
RPA heterotrimerR-HSA-5358599 (Reactome)
RPA heterotrimerR-HSA-5358619 (Reactome)
RPA:DNA containing single strand gapArrowR-HSA-5358599 (Reactome)
RPA:DNA containing single strand gapArrowR-HSA-5358619 (Reactome)
RPA:DNA containing single strand gapR-HSA-5358579 (Reactome)
Repaired double-stranded DNAArrowR-HSA-5358592 (Reactome)
dATPR-HSA-5358579 (Reactome)
dCTPR-HSA-5358579 (Reactome)
dGTPR-HSA-5358579 (Reactome)
dTTPR-HSA-5358579 (Reactome)
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