Human Gene MSH2 (ENST00000233146.7_4) from GENCODE V47lift37
Description: 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. Recruits DNA helicase MCM9 to chromatin which unwinds the mismatch containing DNA strand (PubMed:26300262). 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. (from UniProt P43246) Gencode Transcript: ENST00000233146.7_4 Gencode Gene: ENSG00000095002.16_13 Transcript (Including UTRs) Position: hg19 chr2:47,630,295-47,710,362 Size: 80,068 Total Exon Count: 16 Strand: + Coding Region Position: hg19 chr2:47,630,331-47,710,088 Size: 79,758 Coding Exon Count: 16
ID:MSH2_HUMAN DESCRIPTION: RecName: Full=DNA mismatch repair protein Msh2; Short=hMSH2; AltName: Full=MutS protein homolog 2; 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. SUBUNIT: 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. INTERACTION: P39875:EXO1 (xeno); NbExp=2; IntAct=EBI-355888, EBI-6738; P20585:MSH3; NbExp=4; IntAct=EBI-355888, EBI-1164205; P52701:MSH6; NbExp=4; IntAct=EBI-355888, EBI-395529; Q8IY92:SLX4; NbExp=5; IntAct=EBI-355888, EBI-2370740; SUBCELLULAR LOCATION: Nucleus (Potential). TISSUE SPECIFICITY: Ubiquitously expressed. PTM: Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway. PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. DISEASE: Defects in MSH2 are the cause of hereditary non-polyposis colorectal cancer type 1 (HNPCC1) [MIM:120435]. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers 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. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an 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. MSH2 mutations may predispose to hematological malignancies and multiple cafe-au-lait spots. DISEASE: Defects in MSH2 are a cause of Muir-Torre syndrome (MRTES) [MIM:158320]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. DISEASE: Defects in MSH2 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089]. SIMILARITY: Belongs to the DNA mismatch repair MutS family. SEQUENCE CAUTION: Sequence=AAC27930.1; Type=Frameshift; Positions=417; Note=The frameshift is caused by a single nucleotide deletion which is found in a HNPCC kindred; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MSH2ID340ch2p22.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MSH2"; WEB RESOURCE: Name=Hereditary non-polyposis colorectal cancer db; URL="http://www.nfdht.nl/"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/msh2/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00488 - MutS domain V PF01624 - MutS domain I PF05188 - MutS domain II PF05190 - MutS family domain IV PF05192 - MutS domain III
SCOP Domains: 48334 - DNA repair protein MutS, domain III 103657 - BAR/IMD domain-like 48163 - An anticodon-binding domain of class I aminoacyl-tRNA synthetases 52540 - P-loop containing nucleoside triphosphate hydrolases 53150 - DNA repair protein MutS, domain II 55271 - DNA repair protein MutS, domain I
ModBase Predicted Comparative 3D Structure on P43246
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001701 in utero embryonic development GO:0002204 somatic recombination of immunoglobulin genes involved in immune response GO:0006119 oxidative phosphorylation GO:0006281 DNA repair GO:0006298 mismatch repair GO:0006301 postreplication repair GO:0006302 double-strand break repair GO:0006311 meiotic gene conversion GO:0006974 cellular response to DNA damage stimulus GO:0007050 cell cycle arrest GO:0007281 germ cell development GO:0008340 determination of adult lifespan GO:0008584 male gonad development GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage GO:0010165 response to X-ray GO:0010224 response to UV-B GO:0016446 somatic hypermutation of immunoglobulin genes GO:0016447 somatic recombination of immunoglobulin gene segments GO:0019724 B cell mediated immunity GO:0030183 B cell differentiation GO:0031573 intra-S DNA damage checkpoint GO:0042771 intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator GO:0043524 negative regulation of neuron apoptotic process GO:0043570 maintenance of DNA repeat elements GO:0045128 negative regulation of reciprocal meiotic recombination GO:0045190 isotype switching GO:0045910 negative regulation of DNA recombination GO:0048298 positive regulation of isotype switching to IgA isotypes GO:0048304 positive regulation of isotype switching to IgG isotypes GO:0051096 positive regulation of helicase activity
AK304496 - Homo sapiens cDNA FLJ51193 complete cds, highly similar to DNA mismatch repair protein Msh2. LF385225 - JP 2014500723-A/192728: Polycomb-Associated Non-Coding RNAs. AK222860 - Homo sapiens mRNA for mutS homolog 2 variant, clone: HEP15490. AK296831 - Homo sapiens cDNA FLJ57316 complete cds, highly similar to DNA mismatch repair protein Msh2. AK297763 - Homo sapiens cDNA FLJ50998 complete cds, highly similar to DNA mismatch repair protein Msh2. AK223284 - Homo sapiens mRNA for mutS homolog 2 variant, clone: SYN05289. BX649122 - Homo sapiens mRNA; cDNA DKFZp686M1937 (from clone DKFZp686M1937). BC021566 - Homo sapiens mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli), mRNA (cDNA clone MGC:31906 IMAGE:4110354), complete cds. U03911 - Human mutator gene (hMSH2) mRNA, complete cds. AK299667 - Homo sapiens cDNA FLJ51069 complete cds, highly similar to DNA mismatch repair protein Msh2. AK310679 - Homo sapiens cDNA, FLJ17721. MG674653 - Homo sapiens DNA mismatch repair protein Msh2 transcript variant (MSH2) mRNA, complete cds. MA620802 - JP 2018138019-A/192728: Polycomb-Associated Non-Coding RNAs. BC012599 - Homo sapiens mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli), mRNA (cDNA clone IMAGE:4281235), with apparent retained intron. U04045 - Human (hMSH2) mRNA, complete cds. JD545145 - Sequence 526169 from Patent EP1572962. L47574 - Homo sapiens mismatch repair protein (MSH2) mRNA, with a Q288stop mutation. L47575 - Homo sapiens DNA mismatch repair protein (MSH2) mRNA, with a deletion mutation causing a premature stop. L47576 - Homo sapiens DNA mismatch repair protein (MSH2) mRNA, with a 1 base pair deletion, causing hereditary nonpolyposis colorectal cancer. L47577 - Homo sapiens DNA mismatch repair protein (MSH2) mRNA, with a Gln387stop mutation, causing hereditary nonpolyposis colorectal cancer. L47578 - Homo sapiens DNA mismatch repair protein (MSH2) mRNA, with a 1 base pair insertion, causing hereditary nonpolyposis colorectal cancer. L47579 - Homo sapiens DNA mismatch repair protein (MSH2) mRNA, with a 1 base pair insertion at base 1662, causing hereditary nonpolyposis colorectal cancer. L47580 - Homo sapiens DNA mismatch repair protein (MSH2) mRNA, with a 1 base pair deletion at base 2413, causing hereditary nonpolyposis colorectal cancer. L47581 - Homo sapiens DNA mismatch repair protein (MSH2) allele Arg96His mRNA, complete cds. L47582 - Homo sapiens DNA mismatch repair protein (MSH2) allele Leu556Leu mRNA, complete cds. L47583 - Homo sapiens DNA mismatch repair protein (MSH2) allele Lys579Lys mRNA, complete cds. JD379012 - Sequence 360036 from Patent EP1572962. JD373354 - Sequence 354378 from Patent EP1572962. AK311330 - Homo sapiens cDNA, FLJ18372. DQ892558 - Synthetic construct clone IMAGE:100005188; FLH187495.01X; RZPDo839H1172D mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2) gene, encodes complete protein. DQ895772 - Synthetic construct Homo sapiens clone IMAGE:100010232; FLH187491.01L; RZPDo839H1162D mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2) gene, encodes complete protein. AB489153 - Synthetic construct DNA, clone: pF1KB3091, Homo sapiens MSH2 gene for mutS homolog 2, colon cancer, nonpolyposis type 1, without stop codon, in Flexi system. BC001122 - Homo sapiens, Similar to mutS (E. coli) homolog 2 (colon cancer, nonpolyposis type 1), clone IMAGE:2989085, mRNA. CU692370 - Synthetic construct Homo sapiens gateway clone IMAGE:100017850 5' read MSH2 mRNA. KJ891640 - Synthetic construct Homo sapiens clone ccsbBroadEn_01034 MSH2 gene, encodes complete protein. KR710595 - Synthetic construct Homo sapiens clone CCSBHm_00014183 MSH2 (MSH2) mRNA, encodes complete protein. KR710596 - Synthetic construct Homo sapiens clone CCSBHm_00014276 MSH2 (MSH2) mRNA, encodes complete protein. KR710597 - Synthetic construct Homo sapiens clone CCSBHm_00014330 MSH2 (MSH2) mRNA, encodes complete protein. KR710598 - Synthetic construct Homo sapiens clone CCSBHm_00014377 MSH2 (MSH2) mRNA, encodes complete protein. DQ648894 - Homo sapiens MSH2-Ex3 isoform (MSH2) mRNA, partial cds, alternatively spliced. LF342449 - JP 2014500723-A/149952: Polycomb-Associated Non-Coding RNAs. LF342450 - JP 2014500723-A/149953: Polycomb-Associated Non-Coding RNAs. LF342451 - JP 2014500723-A/149954: Polycomb-Associated Non-Coding RNAs. DQ648895 - Homo sapiens MSH2-Ex5 isoform (MSH2) mRNA, partial cds, alternatively spliced. LF342452 - JP 2014500723-A/149955: Polycomb-Associated Non-Coding RNAs. LF342453 - JP 2014500723-A/149956: Polycomb-Associated Non-Coding RNAs. LF342454 - JP 2014500723-A/149957: Polycomb-Associated Non-Coding RNAs. DQ648896 - Homo sapiens MSH2+ins9a isoform (MSH2) mRNA, partial cds, alternatively spliced. DQ648897 - Homo sapiens MSH2-Ex10 isoform (MSH2) mRNA, partial cds, alternatively spliced. LF342462 - JP 2014500723-A/149965: Polycomb-Associated Non-Coding RNAs. LF342464 - JP 2014500723-A/149967: Polycomb-Associated Non-Coding RNAs. LF342469 - JP 2014500723-A/149972: Polycomb-Associated Non-Coding RNAs. LF342470 - JP 2014500723-A/149973: Polycomb-Associated Non-Coding RNAs. LF342472 - JP 2014500723-A/149975: Polycomb-Associated Non-Coding RNAs. HW469364 - JP 2014500871-A/11: MATERIALS AND METHODS RELATED TO MICRORNA-21, MISMATCH REPAIR, AND COLORECTAL CANCER. HW297781 - JP 2013523126-A/24: MATERIALS AND METHODS RELATED TO MODULATION OF MISMATCH REPAIR AND GENOMIC STABILITY BY MIR-155. JA894000 - Sequence 24 from Patent EP2552547. MA578026 - JP 2018138019-A/149952: Polycomb-Associated Non-Coding RNAs. MA578027 - JP 2018138019-A/149953: Polycomb-Associated Non-Coding RNAs. MA578028 - JP 2018138019-A/149954: Polycomb-Associated Non-Coding RNAs. MA578029 - JP 2018138019-A/149955: Polycomb-Associated Non-Coding RNAs. MA578030 - JP 2018138019-A/149956: Polycomb-Associated Non-Coding RNAs. MA578031 - JP 2018138019-A/149957: Polycomb-Associated Non-Coding RNAs. MA578039 - JP 2018138019-A/149965: Polycomb-Associated Non-Coding RNAs. MA578041 - JP 2018138019-A/149967: Polycomb-Associated Non-Coding RNAs. MA578046 - JP 2018138019-A/149972: Polycomb-Associated Non-Coding RNAs. MA578047 - JP 2018138019-A/149973: Polycomb-Associated Non-Coding RNAs. MA578049 - JP 2018138019-A/149975: Polycomb-Associated Non-Coding RNAs. LF342473 - JP 2014500723-A/149976: Polycomb-Associated Non-Coding RNAs. JD053373 - Sequence 34397 from Patent EP1572962. MA578050 - JP 2018138019-A/149976: Polycomb-Associated Non-Coding RNAs.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein P43246 (Reactome details) participates in the following event(s):
R-HSA-5444511 Formation of MSH2:MSH3 Complex R-HSA-5444516 Formation of MSH2:MSH6 Complex R-HSA-5358513 MSH2:MSH3 binds insertion/deletion loop of 2 bases or more R-HSA-5358525 MSH2:MSH6 binds 1 base mismatch or 1-2 base insertion/deletion loop R-HSA-5358919 MSH2:MSH3 exchanges ADP for ATP R-HSA-5358912 MSH2:MSH6 exchanges ADP for ATP R-HSA-5358545 EXO1 interacts with MSH2:MSH3 (MutSbeta) and MLH1:PMS2 (MutLalpha) R-HSA-5358512 MLH1:PMS2 makes single strand incision near insertion/deletion loop of 2 bases or more R-HSA-5358519 MSH2:MSH3 recruits MLH1:PMS2 to mismatch and interacts with PCNA R-HSA-5358518 MLH1:PMS2 makes single strand incision near 1-2 base mismatch R-HSA-5358510 MSH2:MSH6 recruits MLH1:PMS2 to mismatch and interacts with PCNA R-HSA-5358597 EXO1 interacts with MSH2:MSH6 (MutSalpha) and MLH1:PMS2 (MutLalpha) R-HSA-5358606 Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) R-HSA-5358565 Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) R-HSA-5632927 Defective Mismatch Repair Associated With MSH3 R-HSA-5632968 Defective Mismatch Repair Associated With MSH6 R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes R-HSA-5358508 Mismatch Repair R-HSA-5423599 Diseases of Mismatch Repair (MMR) R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-5632928 Defective Mismatch Repair Associated With MSH2 R-HSA-73894 DNA Repair R-HSA-1643685 Disease R-HSA-212436 Generic Transcription Pathway R-HSA-73857 RNA Polymerase II Transcription R-HSA-74160 Gene expression (Transcription)
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
