MSH6 gene

The MSH6 gene (MSH6 stands for: MutS Homolog 6) is a protein-coding gene localized on chomosome 2p16.3. Transcript variants encoding different isoforms have been described. Associated signaling pathways include DNA repair pathways, the entire network and base excision repair. An important paralog of this gene is MSH2.

The MSH6 gene encodes a member of the MutS family for the repair of DNA mismatches (see mismarch repair system below). In E. coli, the MutS protein helps to recognize mismatched nucleotides before they are repaired. In MutS homologs, there is a highly conserved region of about 150 aa, the so-called Walker A adenine nucleotide binding motif.

The encoded MSH6 protein forms a mismatch recognition complex in heterodimerization with the MSH2 protein, which acts as a bidirectional molecular switch that exchanges ADP and ATP when DNA mismatches are bound and separated.

The encoded protein is a component of the post-replicative DNA mismatch repair system (MMR ).

MSH6 heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches to initiate DNA repair. When bound, MutS alpha bends the DNA helix and shields about 20 base pairs. It recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After binding the mismatch, it forms a ternary complex with the heterodimer MutL alpha, which is thought to be responsible for controlling downstream MMR events, including strand discrimination, excision and resynthesis. ATP binding and hydrolysis play a central role in mismatch repair functions.

ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatching DNA provokes an ADP-->ATP exchange, resulting in a recognizable conformational change that transforms 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 the repair of homologous DNA recombinations.

Recruited to chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated, allowing rapid identification of mismatch repair to initiate the DNA mismatch repair response.

Mutations in the MSH6 gene can be associated with various hereditary tumor entities, such as hereditary non-polyposis colorectal cancer, colorectal carcinoma and endometrial carcinoma. Other diseases associated with MSH6 include Lynch syndrome (see also Muir-Torre syndrome: In Muir-Torre syndrome, a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous gland neoplasia and/or keratoacanthomas and visceral malignancies, germline mutations are usually found in the DNA mismatch repair genes MSH2 and, although less frequently, in MLH1/Mahalingam M 2017).

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