id: PW:0000662
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000662
title: mismatch repair pathway
description_xrefs:
- GO:0006298
- KEGG:map03430
description: DNA mismatch repair (MMR) represents a highly conserved pathway that assures the correct
  base matching of the duplex. Despite the high replication fidelity of polymerases, mismatched bases
  may be introduced into the daughter strand during DNA replication; small deletion/insertion loops may
  be introduced during replication of repetitive DNA tracts. If uncorrected, mismatches will give rise
  to potentially deleterious mutations. MMR pathway has been well studied and characterized in E. coli
  . In eukaryotes, the best characterized system is S. cerevisiae ; human components have been identified
  and assayed in cell extracts and reconstituted systems. E. coli MMR is initiated by recognition of mismatched
  bases by MutS; MutL relays MutS activity to downstream events. Msh proteins are the mammalian counterparts
  of MutS; Mlh and Pms proteins are the counterparts of MutL. Base excision is mediated by Exo1; protection
  of ssDNA and prevention of hairpin formation is provided by Rpa - a trimeric single-stranded DNA-binding
  protein complex. Repair of the single-stranded gap involves re-synthesis and ligation carried out by
  DNA polymerase delta and DNA ligase 1. Several polymerases maintain the integrity of the genome by carrying
  out DNA replication, recombination and repair. Delta and epsilon polymerases are involved in DNA replication
  and in DNA base and strand repair pathways; only delta appears to be specifically involved in MMR. Base
  excision and nucleotide excision are base repair pathways that fix DNA damaged by exogenous or endogenous
  agents. Polymerase delta requires a moving platform; this is provided by the processivity factor Pcna
  (known as the clamp) and a pentameric protein complex Rfc (Replication factor C) that loads it (known
  as the clamp-loader). Rfc binds the ring shaped Pcna in the presence of ATP; ATP-bound Rfc binds DNA
  and this event prompts ATP hydrolysis and ejection of the Rfc complex. The now closed Pcna clamp on
  DNA is in the proper orientation for use by the polymerase. Delta polymerase and Rcf appear to bind/compete
  for the same site on the Pcna clamp. Interactions between components of MMR and between some of these
  components and other proteins have been established; the significance of many remains elusive. And so
  are many of the molecular details of the pathway such as strand specificity and recognition or Rpa clearance
  amongst them. Alterations in MMR pathway have been implicated in colorectal and other forms of cancer.
diagram_image: https://rgd.mcw.edu/pathway/PW0000662/mismatch%20repair%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000662/mismatch%20repair%20pathway/mismatch%20repair%20pathway.gpp
diagram_pathway_links: []
diagram_gene_links:
- id: RGD:1309465
  label: Exo1
- id: RGD:621424
  label: Lig1
- id: RGD:3269
  label: Pcna
diagram_chemicals:
- id: PUBCHEM.COMPOUND:5957
  label: ATP
diagram_edges:
- source: Exo1
  relation: associated_with
  target: Mlh members
- source: Exo1
  relation: associated_with
  target: Msh members
- source: Exo1
  relation: associated_with
  target: Pcna
- source: Lig1
  relation: associated_with
  target: Pcna
- source: Mlh members
  relation: associated_with
  target: Pcna
- source: Msh members
  relation: associated_with
  target: Pcna
- source: Pcna
  relation: associated_with
  target: Rfc complex
- source: Pcna
  relation: associated_with
  target: pold complex
diagram_labels:
- excised base
diagram_other_links:
- href: /wg/home/pathway2/molecular-pathways2/mlh-members
  label: Mlh members
- href: /wg/home/pathway2/molecular-pathways2/msh-members
  label: Msh members
- href: /wg/home/pathway2/molecular-pathways2/pms-members
  label: Pms members
- href: /wg/home/pathway2/molecular-pathways2/pold-complex
  label: pold complex
- href: /wg/home/pathway2/molecular-pathways2/rfc-complex
  label: Rfc complex
- href: /wg/home/pathway2/molecular-pathways2/rpa-complex
  label: Rpa complex
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  citation: Budd ME and Campbell JL, Mutat Res. 2000 Jun 30;451(1-2):241-55.
- id: RGD:5129803
  citation: Bowman GD, etal., FEBS Lett. 2005 Feb 7;579(4):863-7.
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  citation: Kunkel TA and Erie DA, Annu Rev Biochem. 2005;74:681-710.
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- id: RGD:5129968
  citation: Altieri F, etal., Antioxid Redox Signal. 2008 May;10(5):891-937.
- id: RGD:5129996
  citation: Ellenberger T and Tomkinson AE, Annu Rev Biochem. 2008;77:313-38.