MSH2 Gene

The MSH2 gene (MSH2 stands for "MutS Homolog 2") is a protein coding gene located on cytogenetic band 2p21-p16.3 from chromosome 2. The MSH2 gene encodes two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer). These bind to DNA mismatches and thereby initiate DNA repair. The 2p21-p16.3 locus is mutated in hereditary nonpolyposis colorectal cancer (HNPCC). Furthermore, mutations in this locus are associated with Muir-Torre syndrome.

MSH2 encodes two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer). These bind to DNA mismatches and thereby initiate DNA repair. When bound, the heterodimers bend the DNA helix and shield about 20 base pairs. MutS alpha detects single base mismatches and dinucleotide insertion-deletion loops (IDL) in DNA. MutS beta detects larger insertion-deletion loops of up to 13 nucleotides in length. After binding the mismatch, MutS alpha or MutS-beta forms another complex with the heterodimer MutL alpha. Recruits the DNA helicase MCM9 to chromatin, which unwinds the mismatch-containing DNA strand (Traver S et al. 2015).

ATP binding and hydrolysis play a central role in mismatch repair. ATPase activity associated with MutS alpha regulates binding in a manner similar to a molecular switch: mismatched DNA provokes an ADP-->ATP exchange, resulting in a detectable conformational change. This transition is critical for mismatch repair. MutS alpha may also play a role in the repair of homologous DNA recombinations. In melanocytes, it may modulate both UV-B-induced cell cycle regulation and apoptosis.

Muir-Torre syndrome is a variant of Lynch syndrome with cutaneous neoplasms (sebaceous gland enoplasms) and is associated with a high (>80%) lifetime risk of colon cancer.

Upon gene cloning, the MSH2 gene was found to be a human homolog of the E. coli mismatch repair gene MutS. The mismatch repair pathway is a highly conserved biological pathway that plays a key role in maintaining genome stability by correcting base mismatches and insertion/deletion mismatches that occur during DNA replication and recombination (Traver S et al. 2015). Escherichia coli MutS and MutL and their eukaryotic homologs, MutS alpha and MutL alpha, respectively, are the major players in MMR-associated genome maintenance (Sameer AS et al. 2014).

1. Sameer AS et al. (2014) Mismatch repair pathway: molecules, functions, and role in colorectal carcinogenesis. Eur J Cancer Prev. 23:246-257.
2. Traver S et al (2015) MCM9 Is Required for Mammalian DNA Mismatch Repair. Mol Cell 59:831-839.
3. Truninger K et al (2005) Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 128:1160-1171