MSH2 Antibody – Rabbit Monoclonal

This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

Function: Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and 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, and resynthesis. ATP binding and 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 and apoptosis. Ref.16 Ref.17 Ref.18 Ref.20 Ref.23 Ref.29 Ref.32

Subunit structure: Heterodimer consisting of MSH2-MSH6 (MutS alpha) or MSH2-MSH3 (MutS beta). Both heterodimer form a ternary complex with MutL alpha (MLH1-PMS1). Interacts with EXO1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with ATR. Interacts with SLX4/BTBD12; this interaction is direct and links MutS beta to SLX4, a subunit of different structure-specific endonucleases. Interacts with SMARCAD1. Ref.14 Ref.15 Ref.22 Ref.24 Ref.25 Ref.26 Ref.27 Ref.28 Ref.36 Ref.37

Subcellular location: Nucleus

Potential.

Tissue specificity: Ubiquitously expressed. Ref.22

Post-translational modification: Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway. Ref.30

Involvement in disease: Hereditary non-polyposis colorectal cancer 1 (HNPCC1) [MIM:120435]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3 Ref.19 Ref.42 Ref.45 Ref.47 Ref.48 Ref.49 Ref.50 Ref.53 Ref.54 Ref.55 Ref.57 Ref.60 Ref.62 Ref.63 Ref.64 Ref.65 Ref.67 Ref.68 Ref.70 Ref.71 Ref.73 Ref.74 Ref.75 Ref.78 Ref.79 Ref.80 Ref.81 Ref.82 Ref.84 Ref.85 Ref.86 Ref.88 Ref.89 Ref.90 Ref.91 Ref.92 Ref.93 Ref.94 Ref.95 Ref.96 Ref.97 Ref.98 Ref.99 Ref.100 Ref.102 Ref.103 Ref.104 Ref.105 Ref.106 Ref.108Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.4Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids.Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

Sequence similarities: Belongs to the DNA mismatch repair MutS family.

Sequence caution: The sequence AAC27930.1 differs from that shown. Reason: Frameshift at position 417. The frameshift is caused by a single nucleotide deletion which is found in a HNPCC kindred.