DNA mismatch repair protein Msh6; hMSH6; mutS-alpha 160 kD subunit; p160; G/T mismatch-binding protein; GTMBP; GTBP (MSH6 GTBP)

Function

• component of the post-replicative DNA mismatch repair system (MMR)
• recognizes base-pair mismatches, particularly G/T
• heterodimerizes with MSH2 to form mutS alpha, which binds to DNA mismatches thereby initiating DNA repair
• when bound, mutS alpha bends the DNA helix & shields approximately 20 base pairs, & recognizes single base mismatches & dinucleotide insertion-deletion loops (IDL) in the DNA
• after mismatch binding, 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
• the N-terminus is blocked
• phosphorylated upon DNA damage, probably by ATM or ATR
• phosphorylated by PRKCZ, which may prevent mutS alpha degradation by the ubiquitin-proteasome pathway
• heterodimer consisting of MSH2-MSH6 (mutS alpha)
• forms 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

Structure

• belongs to the DNA mismatch repair mutS family
• contains 1 PWWP domain

Compartment

nucleus

Alternative splicing

• named isoforms=2
• GTBP-N, TBP-alt

Pathology

• defects in MSH6 are the cause of
  • hereditary non-polyposis colorectal cancer type 5
  • susceptibility to endometrial cancer [MIM:608089]

More general terms

• helicase (DNA unwinding protein, DNA untwisting protein)
• mutS family protein

Additional terms

• DNA mismatch repair; post-replication repair; DNA loop repair

Component of

• MutS-alpha
• BRCA1-associated genome surveillance complex (BASC)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=2956
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:2956
• OMIM: https://mirror.omim.org/entry/600678
• OMIM: https://mirror.omim.org/entry/608089
• UniProt: http://www.uniprot.org/uniprot/P52701.html