ID:MLH1_HUMAN DESCRIPTION: RecName: Full=DNA mismatch repair protein Mlh1; AltName: Full=MutL protein homolog 1; FUNCTION: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH6) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS- heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis. SUBUNIT: Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). 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 MBD4. Interacts with EXO1 and MTMR15/FAN1. INTERACTION: P63261:ACTG1; NbExp=7; IntAct=EBI-744248, EBI-351292; P07355:ANXA2; NbExp=7; IntAct=EBI-744248, EBI-352622; P07858:CTSB; NbExp=7; IntAct=EBI-744248, EBI-715062; P17661:DES; NbExp=7; IntAct=EBI-744248, EBI-1055572; Q16658:FSCN1; NbExp=7; IntAct=EBI-744248, EBI-351076; Q969T7:NT5C3L; NbExp=3; IntAct=EBI-744248, EBI-2932564; P54278:PMS2; NbExp=3; IntAct=EBI-744248, EBI-1162561; Q13813:SPTAN1; NbExp=7; IntAct=EBI-744248, EBI-351450; P62328:TMSB4X; NbExp=16; IntAct=EBI-744248, EBI-712598; O75152:ZC3H11A; NbExp=3; IntAct=EBI-744248, EBI-748480; SUBCELLULAR LOCATION: Nucleus. TISSUE SPECIFICITY: Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart. DISEASE: Defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 (HNPCC2) [MIM:609310]. 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, and accounts for 15% of all colon cancers. 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. DISEASE: Defects in MLH1 are a cause of mismatch repair cancer syndrome (MMRCS) [MIM:276300]; also known as Turcot syndrome or brain tumor-polyposis syndrome 1 (BTPS1). MMRCS is an autosomal dominant disorder characterized by malignant tumors of the brain associated with multiple colorectal adenomas. Skin features include sebaceous cysts, hyperpigmented and cafe au lait spots. DISEASE: Defects in MLH1 are a cause of Muir-Torre syndrome (MRTES) [MIM:158320]. Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. DISEASE: Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast. DISEASE: Defects in MLH1 are a cause of susceptibility to endometrial cancer (ENDMC) [MIM:608089]. DISEASE: Note=Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by HNPCC but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease. SIMILARITY: Belongs to the DNA mismatch repair MutL/HexB family. WEB RESOURCE: Name=Hereditary non-polyposis colorectal cancer db; URL="http://www.nfdht.nl/"; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/MLH1ID149ch3p21.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/MLH1"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/mlh1/";
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.
ModBase Predicted Comparative 3D Structure on P40692
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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.
KJ891625 - Synthetic construct Homo sapiens clone ccsbBroadEn_01019 MLH1 gene, encodes complete protein. KR709635 - Synthetic construct Homo sapiens clone CCSBHm_00004400 MLH1 (MLH1) mRNA, encodes complete protein. KR709636 - Synthetic construct Homo sapiens clone CCSBHm_00004465 MLH1 (MLH1) mRNA, encodes complete protein. KR709637 - Synthetic construct Homo sapiens clone CCSBHm_00004520 MLH1 (MLH1) mRNA, encodes complete protein. KR709638 - Synthetic construct Homo sapiens clone CCSBHm_00004554 MLH1 (MLH1) mRNA, encodes complete protein. AK302807 - Homo sapiens cDNA FLJ55289 complete cds, highly similar to DNA mismatch repair protein Mlh1. LP966778 - Sequence 3 from Patent EP3194625. BC006850 - Homo sapiens mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli), mRNA (cDNA clone MGC:5172 IMAGE:3451538), complete cds. JD520865 - Sequence 501889 from Patent EP1572962. U07418 - Human DNA mismatch repair (hmlh1) mRNA, complete cds. DQ648888 - Homo sapiens MLH1+ins1a isoform (MLH1) mRNA, complete cds, alternatively spliced. U07343 - Homo sapiens DNA mismatch repair protein homolog (MLH1) mRNA, complete cds. AK316264 - Homo sapiens cDNA, FLJ79163 complete cds, highly similar to DNA mismatch repair protein Mlh1. AK312609 - Homo sapiens cDNA, FLJ92988, highly similar to Homo sapiens mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1), mRNA. AK222810 - Homo sapiens mRNA for MutL protein homolog 1 variant, clone: HEP04585. AB527828 - Synthetic construct DNA, clone: pF1KB5764, Homo sapiens MLH1 gene for mutL homolog 1, colon cancer, nonpolyposis type 2, without stop codon, in Flexi system. EU176562 - Synthetic construct Homo sapiens clone IMAGE:100011379; FLH169778.01L; RZPDo839G0195D mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1) gene, encodes complete protein. EU176254 - Synthetic construct Homo sapiens clone IMAGE:100006368; FLH169785.01X; RZPDo839D09250D mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1) gene, encodes complete protein. AY517558 - Homo sapiens hypothetical rhabdomyosarcoma antigen MU-RMS-40.5 mRNA, partial cds. AK311326 - Homo sapiens cDNA, FLJ18368. AB209848 - Homo sapiens mRNA for MutL protein homolog 1 variant protein. BX648844 - Homo sapiens mRNA; cDNA DKFZp686I14153 (from clone DKFZp686I14153). AK295359 - Homo sapiens cDNA FLJ50524 complete cds, highly similar to DNA mismatch repair protein Mlh1. AK316074 - Homo sapiens cDNA, FLJ78973 complete cds, highly similar to DNA mismatch repair protein Mlh1. AK298583 - Homo sapiens cDNA FLJ50608 complete cds, highly similar to DNA mismatch repair protein Mlh1. AK311365 - Homo sapiens cDNA, FLJ18407. AK298324 - Homo sapiens cDNA FLJ50603 complete cds, highly similar to DNA mismatch repair protein Mlh1. DQ648889 - Homo sapiens MLH1-Ex6 isoform (MLH1) mRNA, partial cds, alternatively spliced. DQ648891 - Homo sapiens MLH1-Ex(9-10) isoform (MLH1) mRNA, partial cds, alternatively spliced. DQ648890 - Homo sapiens MLH1-Ex10 isoform (MLH1) mRNA, partial cds, alternatively spliced. EU188672 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188667 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188669 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188670 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188668 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188671 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188676 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. S77856 - hMLH1=DNA mismatch repair protein MutL homolog {alternatively spliced} [human, peripheral bood lymphocytes, mRNA Partial, 60 nt]. BC005833 - Homo sapiens mRNA similar to mutL (E. coli) homolog 1 (colon cancer, nonpolyposis type 2) (cDNA clone IMAGE:2962831). BC005866 - Homo sapiens mRNA similar to mutL (E. coli) homolog 1 (colon cancer, nonpolyposis type 2) (cDNA clone IMAGE:2962831). CQ873804 - Sequence 223 from Patent WO2004076622. DD413641 - Regulation of Mammalian Cells. EU188673 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. DQ648892 - Homo sapiens MLH1-Ex(15-18) isoform (MLH1) mRNA, partial cds, alternatively spliced. DQ648893 - Homo sapiens MLH1-Ex(14-18) isoform (MLH1) mRNA, partial cds, alternatively spliced. EU188675 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188674 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188665 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. EU188666 - Homo sapiens MutL-like 1 protein (MLH1) mRNA, partial cds, alternatively spliced. CQ873806 - Sequence 225 from Patent WO2004076622. DD413643 - Regulation of Mammalian Cells. JD549230 - Sequence 530254 from Patent EP1572962. HW297780 - JP 2013523126-A/23: MATERIALS AND METHODS RELATED TO MODULATION OF MISMATCH REPAIR AND GENOMIC STABILITY BY MIR-155. JA893999 - Sequence 23 from Patent EP2552547.
Biochemical and Signaling Pathways
Reactome (by CSHL, EBI, and GO)
Protein P40692 (Reactome details) participates in the following event(s):
R-HSA-5444523 Formation of MSH1:PMS2 Complex R-HSA-5358510 MSH2:MSH6 recruits MLH1:PMS2 to mismatch and interacts with PCNA 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-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-5358597 EXO1 interacts with MSH2:MSH6 (MutSalpha) and MLH1:PMS2 (MutLalpha) R-HSA-912446 Meiotic recombination R-HSA-5358565 Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha) R-HSA-5632987 Defective Mismatch Repair Associated With PMS2 R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes R-HSA-5358606 Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta) R-HSA-1500620 Meiosis R-HSA-5358508 Mismatch Repair R-HSA-5423599 Diseases of Mismatch Repair (MMR) R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-5545483 Defective Mismatch Repair Associated With MLH1 R-HSA-1474165 Reproduction R-HSA-1640170 Cell Cycle 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 
