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DNA mismatch repair protein Msh2; hMSH2; mutS protein homolog 2 (MSH2)

Function: - component of the post-replicative DNA mismatch repair system (MMR) - all mismatches in DNA base pairs require the MSH2 for repair - forms two different heterodimers: a) mutS alpha (MSH2-MSH6 heterodimer) b) mutS beta (MSH2-MSH3 heterodimer) - heterodimers bind to DNA mismatches thus initiating DNA repair - when bound, heterodimers bend the DNA helix & shield approximately 20 base pairs - mutS alpha recognizes single base mismatches & dinucleotide insertion-deletion loops (IDL) in the DNA - mutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long - after mismatch binding, mutS alpha or beta forms a ternary complex with the mutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, & resynthesis - ATP binding & hydrolysis play a pivotal role in mismatch repair functions - the ATPase activity associated with mutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts mutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone - this transition is crucial for mismatch repair - mutS alpha may also play a role in DNA homologous recombination repair - in melanocytes, may modulate both UV-B-induced cell cycle regulation & apoptosis - phosphorylated by PRKCZ, which may prevent mutS alpha degradation by the ubiquitin-proteasome pathway - phosphorylated upon DNA damage, probably by ATM or ATR - heterodimer consisting of MSH2-MSH6 (mutS alpha) or MSH2- MSH3 (mutS beta) - both heterodimers form a ternary complex with mutL alpha (MLH1-PMS1) - interacts with EXO1 - part of the BRCA1-associated genome surveillance complex (BASC) - this association could be a dynamic process changing throughout the cell cycle & within subnuclear domains - interacts with ATR - interacts with BTBD12/SLX4; this interaction is direct & links mutS beta to SLX4, a subunit of different structure-specific endonucleases Structure: belongs to the DNA mismatch repair mutS family Compartment: nucleus (putative) Expression: ubiquitously expressed Pathology: - defects in MSH2 are the cause of a) hereditary non-polyposis colorectal cancer type 1 b) Muir-Torre syndrome c) susceptibility to endometrial cancer [MIM:608089]

Interactions

molecular events

Related

MSH2 gene

General

mutS family protein phosphoprotein

Properties

SIZE: entity length = 934 aa MW = 105 kD MOTIF: EXO1 interaction {601-671} ATP-binding site NAME: ATP-binding site SITE: 669-676 binding site EFFECTOR-BOUND: DNA mismatch repair protein Msh6 Ser phosphorylation site {S860}

Database Correlations

OMIM correlations MORBIDMAP 609309 UniProt P43246 PFAM correlations Entrez Gene 4436 Kegg hsa:4436

References

  1. UniProt :accession P43246
  2. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/MSH2ID340ch2p22.html
  3. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/MSH2
  4. Hereditary non-polyposis colorectal cancer db http://www.nfdht.nl/
  5. NIEHS-SNPs http://egp.gs.washington.edu/data/msh2/
  6. Karran P. Appropriate partners make good matches. Science. 1995 Jun 30;268(5219):1857-8. Review. PMID: 7604258

Component-of

BRCA1-associated genome surveillance complex (BASC)