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Gene Model: Msh2

NomenclatureGenomic Location
SymbolMsh2Chromosome2
NameDNA mismatch repair protein Msh2Linkage mapunknown
SpeciesDracomimus familiarisGenome Coordinates2: 62 Mbp

Molecular 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.

Molecular Function Terms:

binding
   nucleic acid binding
      DNA binding
         structure-specific DNA binding
            DNA secondary structure binding
            double-stranded DNA binding
               mismatched DNA binding
   protein binding
      enzyme binding

catalytic activity
   hydrolase activity
      hydrolase activity, acting on acid anhydrides
         hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides
            pyrophosphatase activity
               nucleoside-triphosphatase activity
                  ATPase activity

Human Disease Association

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.

Defects in MSH2 are a cause of Muir-Torre syndrome (MuToS) [MIM:158320]; also abbreviated MTS. MuToS is a rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy.

Defects in MSH2 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089].

Defects in MSH2 are a cause of hereditary non-polyposis colorectal cancer type 8 (HNPCC8) [MIM:613244]. HNPCC is a 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=HNPCC8 results from heterozygous deletion of 3-prime exons of EPCAM and intergenic regions directly upstream of MSH2, resulting in transcriptional read-through and epigenetic silencing of MSH2 in tissues expressing EPCAM.

Predicted Transcript
     1 GCCGCCGCTTCCCCGCGCGAGGGCTGCTGGCCCGAGGGGACGGTGGCGGAGACGGGCTTC
    61 GTGCGCGCCGTGCTCAGCCTCCCGGAGAAGCCCAGCACCACCATCCGCTTCTTCGAGCGG
   121 GGCGACTACTACACCGTCCACGGCACCGATGCCTTCTTGGCGGCTTCGGAGGTCTTCAAG
   181 ACACGGGGCGTCATCCGGGCGCTGGGGAAAGGACCCCGGACGCTTGATAGTGTTGCCCTT
   241 AGCAAGAGTAATTTCGAATCATTTTTGAGAGATCTTCTCCTGGTGCGTCAATACAGGGCT
   301 GAGGTGTACAAGAACAAAGCAGGAAACAAATCCACCAAGGAGAGTGAATGGTACCTGGCC
   361 TACAAGGGTTCTCCAGGGAACATTGCCCAATTTGAGGATGTTCTGTTTGGCAACCATGAC
   421 ATATCCTCATCTGTTGGTGTTATGGGCATTAAGCTGTTGTCAGCTGATGGACAAAAAGTT
   481 GTTGGAGTTGGGTTTGTAGATACTTTAATGAGGAAGCTGGAAGTATGTGAGTTTGTAGAC
   541 AACGAACAATTTTCAAATCTTGAAGCTCTGCTAGTTCAGATGGGACCAAAGGAATGTTTG
   601 CTACCTATGGGAGAAAATGGTGCAGATATGGAGAAGCTGAGACAGCAGTCCATTCAAAGG
   661 GGAGGAATTCTGATTACAAACAAGAAAAAAAGTGATTTTTTACCAAAAGACATCACTCAA
   721 GATCTCAACCGTTTATTGAGATCAAAAAAGAAAGAGCATGTGTCTAGTGCAGCATTGCCT
   781 GAGATGGACAAACAGGTTGCCATCTCTTCCTTGGCAGCGGCAATTAAGTATTTAGAGCTC
   841 TTAAATGATGACTCTAATTTTGGACAGTTTGAACTCTCTACCTTTGACCTCAACCAGTAC
   901 ATGACACTTGATCATGCTGCTGCCAGAGCCCTTAACCTTTTCCCGGGTTCATCAGGTAAC
   961 ACCCAAAGTACACAGTCTCTATCTGGATTGTTAAATAAGTGCAAAACACCTCAAGGACAG
  1021 AGGCTGGTGAACCAGTGGATCAAACAGCCCTTGATGGACAAGAACAAAATAGAGGAAAGG
  1081 TTAAATTTGGTTGAAGCCTTTGTAGAAGATGCAGAGCTAAGGCAGTCTCTTCAAGAAGAC
  1141 ATCCTCCGTCGATTTCCAGACTTCAGTCGAATAGCAAAAAAATTTCAGAAGAAGGCCACT
  1201 TTGCAGGATTGTTACAAAATATACCAGTCTGTTAATCAGATACCTAATGTGATTCATGTA
  1261 CTGGGCAAAACTGATGGAAACCATGATATGCTGTTGGAAGCAGTGTTTATAAGGCCTCTT
  1321 AAGGAGCTACACTCAGATTTCTCTAATTTCCAAATGATGATTGAAGAAACTTTGGACATG
  1381 AATACGGTTGAGAATCATGAATACCTTGTGAAGCCTTCTATTGATCCAAACCTTGCTGGC
  1441 ATAAGAAAAGTCATGGACAAATTAGAAGAAAAAATGCGAGGTGCACTGAAGACTGCAGCC
  1501 TCAGAGCTAAGTCTGGAAGCTGGGAAGAGCATCAAATTGGAATGCAATGCTCAGTATGGA
  1561 CATCATTTCCGAATTACCTACAGAGAGGAGAAGGTTCTGCGAAACAATCTCAAATATAAG
  1621 GTGCTGGAAACACAGAAGAATGGAGTGAAGTTCTCCAACATATACAGTGCATTGAAAGAC
  1681 TTGAATGAGGAATACATAAAGAACAGAAAGGAGTATGAAGAAATGCAAGATGTTGTTGTT
  1741 AAAGAAATCATCAATGTTGCATCAGGTTACAAAGAGCCTATACAACGCCTGAACGATGTC
  1801 ATCGCCCAGCTGGACGCTGTGGTCAGCTTTGCTCAAGCCTCTAATGCGGCACCAATGCCA
  1861 TACGTGCGCCCCACAATTCTGGAAAAGGGGGAAGGGGGCATTGTGCTGAAAGCTGCGAGA
  1921 CACCCTTGCATTGAGGTCCAAGATGATGTTTCCTTCATCCCCAATGATGTGACCTTTGAG
  1981 AAGGGCAAGCAGATGTTCCATATCATTACTGGTCCAAATATGGGAGGGAAGTCAACCTAC
  2041 ATCCGACAAGCTGGTGTCATTGTTCTTATGGCTCAAATTGGATGTTTTGTGCCATGCGAT
  2101 TCTGCAGATATAACAATTGTCGATTGCATCCTTGCACGAGTAGGAGCTGGAGATAGTCAG
  2161 CTGAAAGGAGTGTCTACCTTCATGGCAGAAATGTTGGAGACATCTTCCATCCTTCGAACT
  2221 GCAACAGAAAATTCCCTGATAATCATCGATGAATTGGGGAGAGGAACATCTACATATGAC
  2281 GGGTTTGGATTAGCCTGGGCAATCTCAGAATATATTGCCACTAAAATTGGAGCCTTTTGC
  2341 ATGTTTGCCACTCATTTCCATGAACTGACGGCACTCGATGAAGAAATTCCAACTGTGAAT
  2401 AACTTACACGTCACAGCACTAACCACAGACGACACCCTCACAATGTTGTACCGTGTGAAA
  2461 AAAGGGGTTTGCGATCAGAGCTTTGGTATCCATGTAGCAGAGCTAGCTGCTTTTCCCAAG
  2521 CATGTAATAGAGAATGCCAAGGCAAAGGCTCTGGAGTTAGAGGAATTCCAGAGTATTGGA
  2581 AACCCTGAAGGAAAAGAGGAGGATGGTGATGGGGAGCCAGCAGCCAAGAAATGCTACAGA
  2641 GAGAAGGAGGAAGGTGAAAAAATAATCCAGGATTTCCTTACTAAAGTGAAAGCGATGCCC
  2701 CTGGAAGATATGTCTGAGACAGACATCCAGACCAAACTGAAAGAACTGAAAAATGAGGTT
  2761 CTAGCATTTAACAACAGCTTTGTAAACGAAATCCTTTCCCGAACAAAAGTTGTGTCATAA

Predicted Protein Product
AAASPREGCWPEGTVAETGFVRAVLSLPEKPSTTIRFFERGDYYTVHGTDAFLAASEVFK
TRGVIRALGKGPRTLDSVALSKSNFESFLRDLLLVRQYRAEVYKNKAGNKSTKESEWYLA
YKGSPGNIAQFEDVLFGNHDISSSVGVMGIKLLSADGQKVVGVGFVDTLMRKLEVCEFVD
NEQFSNLEALLVQMGPKECLLPMGENGADMEKLRQQSIQRGGILITNKKKSDFLPKDITQ
DLNRLLRSKKKEHVSSAALPEMDKQVAISSLAAAIKYLELLNDDSNFGQFELSTFDLNQY
MTLDHAAARALNLFPGSSGNTQSTQSLSGLLNKCKTPQGQRLVNQWIKQPLMDKNKIEER
LNLVEAFVEDAELRQSLQEDILRRFPDFSRIAKKFQKKATLQDCYKIYQSVNQIPNVIHV
LGKTDGNHDMLLEAVFIRPLKELHSDFSNFQMMIEETLDMNTVENHEYLVKPSIDPNLAG
IRKVMDKLEEKMRGALKTAASELSLEAGKSIKLECNAQYGHHFRITYREEKVLRNNLKYK
VLETQKNGVKFSNIYSALKDLNEEYIKNRKEYEEMQDVVVKEIINVASGYKEPIQRLNDV
IAQLDAVVSFAQASNAAPMPYVRPTILEKGEGGIVLKAARHPCIEVQDDVSFIPNDVTFE
KGKQMFHIITGPNMGGKSTYIRQAGVIVLMAQIGCFVPCDSADITIVDCILARVGAGDSQ
LKGVSTFMAEMLETSSILRTATENSLIIIDELGRGTSTYDGFGLAWAISEYIATKIGAFC
MFATHFHELTALDEEIPTVNNLHVTALTTDDTLTMLYRVKKGVCDQSFGIHVAELAAFPK
HVIENAKAKALELEEFQSIGNPEGKEEDGDGEPAAKKCYREKEEGEKIIQDFLTKVKAMP
LEDMSETDIQTKLKELKNEVLAFNNSFVNEILSRTKVVS
Protein Alignment to Mouse
sp|P43247|MSH2_MOUSE DNA mismatch repair protein Msh2 OS=Mus musculus GN=Msh2
            PE=2 SV=1
      MGI:101816 Msh2 mutS homolog 2 (E. coli) (Chr 17)
        Length = 935

 Score = 3293 (1164.3 bits), Expect = 0., P = 0.
 Identities = 643/937 (68%), Positives = 763/937 (81%)

Query:     2 AASPREGCWPEGTVAETGFVRAVLSLPEKPSTTIRFFERGDYYTVHGTDAFLAASEVFKT 61
             A  P+E    EG  AE GFVR    +PEKPSTT+R F+RGD+YT HG DA LAA EVFKT
Sbjct:     2 AVQPKETLQLEGA-AEAGFVRFFEGMPEKPSTTVRLFDRGDFYTAHGEDALLAAREVFKT 60

Query:    62 RGVIRALGK-GPRTLDSVALSKSNFESFLRDLLLVRQYRAEVYKNKAGNKSTKESEWYLA 120
             +GVI+ +G  G +TL SV LSK NFESF++DLLLVRQYR EVYKNKAGNK++KE+EWYLA
Sbjct:    61 QGVIKYMGPAGSKTLQSVVLSKMNFESFVKDLLLVRQYRVEVYKNKAGNKASKENEWYLA 120

Query:   121 YKGSPGNIAQFEDVLFGNHDISSSVGVMGIKLLSADGQKVVGVGFVDTLMRKLEVCEFVD 180
             +K SPGN++QFED+LFGN+D+S+SVGVMGIK+   DGQ+ VGVG+VD+  RKL +CEF +
Sbjct:   121 FKASPGNLSQFEDILFGNNDMSASVGVMGIKMAVVDGQRHVGVGYVDSTQRKLGLCEFPE 180

Query:   181 NEQFSNLEALLVQMGPKECLLPMGENGADMEKLRQQSIQRGGILITNKKKSDFLPKDITQ 240
             N+QFSNLEALL+Q+GPKEC+LP GE   DM KLRQ  IQRGGILIT +K++DF  KDI Q
Sbjct:   181 NDQFSNLEALLIQIGPKECVLPGGETTGDMGKLRQV-IQRGGILITERKRADFSTKDIYQ 239

Query:   241 DLNRLLRSKKKEHVSSAALPEMDKQVAISSLAAAIKYLELLNDDSNFGQFELSTFDLNQY 300
             DLNRLL+ KK E ++SAALPEM+ QVA+SSL+A IK+LELL+DDSNFGQFEL+TFD +QY
Sbjct:   240 DLNRLLKGKKGEQINSAALPEMENQVAVSSLSAVIKFLELLSDDSNFGQFELATFDFSQY 299

Query:   301 MTLDHAAARALNLFPGSSGNTQSTQSLSGLLNKCKTPQGQRLVNQWIKQPLMDKNKIEER 360
             M LD AA RALNLF GS  +T  +QSL+ LLNKCKT QGQRLVNQWIKQPLMD+N+IEER
Sbjct:   300 MKLDMAAVRALNLFQGSVEDTTGSQSLAALLNKCKTAQGQRLVNQWIKQPLMDRNRIEER 359

Query:   361 LNLVEAFVEDAELRQSLQEDILRRFPDFSRIAKKFQKKAT-LQDCYKIYQSVNQIPNVIH 419
             LNLVEAFVED+ELRQSLQED+LRRFPD +R+AKKFQ++A  LQDCY++YQ +NQ+P+VI 
Sbjct:   360 LNLVEAFVEDSELRQSLQEDLLRRFPDLNRLAKKFQRQAANLQDCYRLYQGINQLPSVIQ 419

Query:   420 VLGKTDGNHDMLLEAVFIRPLKELHSDFSNFQMMIEETLDMNTVENHEYLVKPSIDPNLA 479
              L K +G H  LL AVF+ PL +L SDFS FQ MIE TLDM+ VENHE+LVKPS DPNL+
Sbjct:   420 ALEKYEGRHQALLLAVFVTPLIDLRSDFSKFQEMIETTLDMDQVENHEFLVKPSFDPNLS 479

Query:   480 GIRKVMDKLEEKMRGALKTAASELSLEAGKSIKLECNAQYGHHFRITYREEKVLRNNLKY 539
              +R+VMD LE+KM+  L  AA  L L+ GK IKL+ +AQ+G++FR+T +EEKVLRNN  +
Sbjct:   480 ELREVMDGLEKKMQSTLINAARGLGLDPGKQIKLDSSAQFGYYFRVTCKEEKVLRNNKNF 539

Query:   540 KVLETQKNGVKFSNIYSALKDLNEEYIKNRKEYEEMQDVVVKEIINVASGYKEPIQRLND 599
               ++ QKNGVKF+N  S L  LNEEY KN+ EYEE QD +VKEI+N++SGY EP+Q LND
Sbjct:   540 STVDIQKNGVKFTN--SELSSLNEEYTKNKGEYEEAQDAIVKEIVNISSGYVEPMQTLND 597

Query:   600 VIAQLDAVVSFAQASNAAPMPYVRPTILEKGEGGIVLKAARHPCIEVQDDVSFIPNDVTF 659
             V+A LDA+VSFA  SNAAP+PYVRP ILEKG+G I+LKA+RH C+EVQD+V+FIPNDV F
Sbjct:   598 VLAHLDAIVSFAHVSNAAPVPYVRPVILEKGKGRIILKASRHACVEVQDEVAFIPNDVHF 657

Query:   660 EKGKQMFHIITGPNMGGKSTYIRQAGVIVLMAQIGCFVPCDSADITIVDCILARVGAGDS 719
             EK KQMFHIITGPNMGGKSTYIRQ GVIVLMAQIGCFVPC+SA+++IVDCILARVGAGDS
Sbjct:   658 EKDKQMFHIITGPNMGGKSTYIRQTGVIVLMAQIGCFVPCESAEVSIVDCILARVGAGDS 717

Query:   720 QLKGVSTFMAEMLETSSILRTATENSLIIIDELGRGTSTYDGFGLAWAISEYIATKIGAF 779
             QLKGVSTFMAEMLET+SILR+AT++SLIIIDELGRGTSTYDGFGLAWAIS+YIATKIGAF
Sbjct:   718 QLKGVSTFMAEMLETASILRSATKDSLIIIDELGRGTSTYDGFGLAWAISDYIATKIGAF 777

Query:   780 CMFATHFHELTALDEEIPTVNNLHVXXXXXXXXXXMLYRVKKGVCDQSFGIHVAELAAFP 839
             CMFATHFHELTAL  +IPTVNNLHV          MLY+VKKGVCDQSFGIHVAELA FP
Sbjct:   778 CMFATHFHELTALANQIPTVNNLHVTALTTEETLTMLYQVKKGVCDQSFGIHVAELANFP 837

Query:   840 KHVIENXXXXXXXXXXFQSIXXXXXXXXXXXXXXAAKKCYREKEEGEKIIQDFLTKVKAM 899
             +HVI            FQ+I              A ++C  E+E+GEKII +FL+KVK +
Sbjct:   838 RHVIACAKQKALELEEFQNIGTSLGCDEAEPA--AKRRCL-EREQGEKIILEFLSKVKQV 894

Query:   900 PLEDMSETDIQTKLKELKNEVLAFNNSFVNEILSRTK 936
             P   MSE  I  KLK+LK EV+A NNSFVNEI+SR K
Sbjct:   895 PFTAMSEESISAKLKQLKAEVVAKNNSFVNEIISRIK 931