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Mismatch repair endonuclease PMS2; PMS1 protein homolog 2; DNA mismatch repair protein PMS2; postmeiotic segregation increased-2 (PMS2, PMSL2)

Function: - component of the post-replicative DNA mismatch repair system - heterodimerizes with MLH1 to form mutL alpha - DNA repair is initiated by mutS alpha (MSH2-MSH6) or mutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then mutL alpha is recruited to the heteroduplex - assembly of the mutL-mutS-heteroduplex ternary complex in presence of RFC & PCNA is sufficient to activate endonuclease activity of PMS2 - it introduces single-strand breaks near the mismatch & thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch - DNA methylation would prevent cleavage & therefore assure that only the newly mutated DNA strand is going to be corrected - mulL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase 3, suggesting that it may play a role to recruit the DNA polymerase 3 to the site of the MMR - also implicated in DNA damage signaling, a process which induces cell cycle arrest & can lead to apoptosis in case of major DNA damages - heterodimer of PMS2 & MLH1 (mutL alpha) - forms a ternary complex with mutS alpha (MSH2-MSH6) or mutS beta (MSH2-MSH3) - part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 & the RAD50-MRE11-NBS1 protein complex; this association could be a dynamic process changing throughout the cell cycle & within subnuclear domains Structure: - belongs to the DNA mismatch repair mutL/hexB family Compartment: nucleus Alternative splicing: named isoforms=4 Pathology: - defects in PMS2 are the cause of hereditary non-polyposis colorectal cancer type 4 - defects in PMS2 are a cause of mismatch repair cancer syndrome (Turcot syndrome) Laboratory: - mismatch repair endonuclease PMS2 in cancer tissue Comparative biology: - PMS2-/PMS2-knockout mice are viable, but male mice are sterile & appear to have a defect in meiosis.

Interactions

molecular events

Related

DNA mismatch repair protein Mlh1; mutL protein homolog 1 (MLH1, COCA2) DNA mismatch repair; post-replication repair; DNA loop repair MLH1+MSH2+MSH6+PMS2 gene deletion, duplication & mutation analysis PMS-2 Ag in tissue PMS2 gene

General

mutL/PMS1 family protein nuclear protein phosphoprotein

Properties

SIZE: entity length = 862 aa MW = 96 kD COMPARTMENT: cell nucleus MOTIF: Tyr phosphorylation site {Y181} Ser phosphorylation site {S403} Thr phosphorylation site {T573}

References

  1. UniProt :accession P54278
  2. Hereditary non-polyposis colorectal cancer db http://www.nfdht.nl/
  3. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/PMS2
  4. Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397-401. Review. PMID: 8533151

Component-of

MutL-alpha

Databases & Figures

OMIM correlations MORBIDMAP 600259 UniProt P54278 PFAM correlations Entrez Gene 5395 Kegg hsa:5395 mismatch repair scheme (v2)