DNA mismatch repair protein MutS-homologue MSH6 (IPR015536)
Short name: DNA_mismatch_repair_MSH6_C
Overlapping homologous superfamilies
- DNA mismatch repair protein MutS/MSH (IPR017261)
- DNA mismatch repair protein MutS-homologue MSH6 (IPR015536)
Mismatch repair contributes to the overall fidelity of DNA replication and is essential for combating the adverse effects of damage to the genome. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex. The post-replicative Mismatch Repair System (MMRS) of Escherichia coli involves MutS (Mutator S), MutL and MutH proteins, and acts to correct point mutations or small insertion/deletion loops produced during DNA replication [PMID: 17919654]. MutS and MutL are involved in preventing recombination between partially homologous DNA sequences. The assembly of MMRS is initiated by MutS, which recognises and binds to mispaired nucleotides and allows further action of MutL and MutH to eliminate a portion of newly synthesized DNA strand containing the mispaired base [PMID: 17599803]. MutS can also collaborate with methyltransferases in the repair of O(6)-methylguanine damage, which would otherwise pair with thymine during replication to create an O(6)mG:T mismatch [PMID: 17951114]. MutS exists as a dimer, where the two monomers have different conformations and form a heterodimer at the structural level [PMID: 17426027]. Only one monomer recognises the mismatch specifically and has ADP bound. Non-specific major groove DNA-binding domains from both monomers embrace the DNA in a clamp-like structure. Mismatch binding induces ATP uptake and a conformational change in the MutS protein, resulting in a clamp that translocates on DNA.
MutS is a modular protein with a complex structure [PMID: 11048711], and is composed of:
- N-terminal mismatch-recognition domain, which is similar in structure to tRNA endonuclease.
- Connector domain, which is similar in structure to Holliday junction resolvase ruvC.
- Core domain, which is composed of two separate subdomains that join together to form a helical bundle; from within the core domain, two helices act as levers that extend towards (but do not touch) the DNA.
- Clamp domain, which is inserted between the two subdomains of the core domain at the top of the lever helices; the clamp domain has a beta-sheet structure.
- ATPase domain (connected to the core domain), which has a classical Walker A motif.
- HTH (helix-turn-helix) domain, which is involved in dimer contacts.
The MutS family of proteins is named after the Salmonella typhimurium MutS protein involved in mismatch repair. Homologues of MutS have been found in many species including eukaryotes (MSH 1, 2, 3, 4, 5, and 6 proteins), archaea and bacteria, and together these proteins have been grouped into the MutS family. Although many of these proteins have similar activities to the E. coli MutS, there is significant diversity of function among the MutS family members. Human MSH has been implicated in non-polyposis colorectal carcinoma (HNPCC) and is a mismatch binding protein [PMID: 8036718].This diversity is even seen within species, where many species encode multiple MutS homologues with distinct functions [PMID: 9722651]. Inter-species homologues may have arisen through frequent ancient horizontal gene transfer of MutS (and MutL) from bacteria to archaea and eukaryotes via endosymbiotic ancestors of mitochondria and chloroplasts [PMID: 17965091].
MSH6 is an ATPase that is part of the MSH2-MSH6 complex and has been shown in Homo sapiens (Human) to bind to mismatched DNA directly in the ADP-bound state [PMID: 9428522]. The MSH6 has members from yeasts, plants, fish, and mammals. After DNA replication, a low level of replication errors exist, including base-pair mismatches. In bacteria, it was shown that MutS acts with MutL, MutH, and UvrD to correct these errors. In Human, it was shown that MSH2 and MSH6 are involved in the BASC complex (BRCA1-associated genome surveillance complex) with many other proteins including MLH1, RAD50, MRE11, NBS1, RFC1, RFC2, RFC4, BRCA1, ATM, and BLM [PMID: 10783165]. In Human, mutations in MSH6 have been shown to be associated with hereditary nonpolyposis colon cancer [PMID: 7604266] and endometrial cancer [PMID: 11333868].
GO:0006298 mismatch repair
No terms assigned in this category.
No terms assigned in this category.
- PTHR11361:SF31 (PTHR11361:SF31)