Gene content
Symbol	MLH1 ( by HUGO)
Name	MutL Homolog 1
Category	Tumor suppressor gene
Alias	MutL Homolog 1 COCA2 HNPCC2 MutL (E. Coli) Homolog 1 (Colon Cancer Nonpolyposis Type 2) MutL Homolog 1 Colon Cancer Nonpolyposis Type 2 (E. Coli) FCC2 HNPCC DNA Mismatch Repair Protein Mlh1 hMLH1 MutL Homolog 1 Colon Cancer Nonpolyposis Type 2 MutL Protein Homolog 1
Cytogenetic band	NCBI: 3p21.3    Ensembl: 3p22.2
Protein information	MLH1_HUMAN Size: 756 amino acids Mass: 84601 Da 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 2 PDB 3D structures from [IMAGE] and Proteopedia [IMAGE] for MLH1: 3NA3 (3D) [IMAGE] 3RBN (3D) [IMAGE] Tissue specificity: Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart [IMAGE] Pathway & Disease-focused RT2 Profiler PCR Arrays including MLH1 (see all 9): Oncogenes & Tumor Suppressor Genes in human mouse rat Lung Cancer in human mo Function: UniProtKB/Swiss-Prot Summary: MLH1_HUMAN, P40692 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 Similarity: Belongs to the DNA mismatch repair MutL/HexB family [IMAGE]

Protein Domain/Family
Source	ID	Domain	Name	Type
InterPro	IPR002099	DNA_mismatch_repair_fam	DNA mismatch repair protein	Family
	IPR003594	HATPase_ATP-bd	ATP-binding region, ATPase-like	Domain
	IPR011186	DNA_mismatch_repair_MLH1	DNA mismatch repair protein Mlh1	Family
Blocks	IPB002099	DNA mismatch repair protein	DNA mismatch repair protein

Gene Ontology
Type	Term	Evidence	Source	Pub
Cellular Component	membrane	IDA	GOA	19946888
	nucleus	IC	GOA	11809883
Molecular Function	contributes_to MutSalpha complex binding	IDA	GOA	16403449
	contributes_to protein binding	IPI	GOA	16403449
	contributes_to single-stranded DNA binding	IDA	GOA	11809883
	protein binding	IPI	GOA	11427529

Disorder & Mutation
Source	Disease
SWISS-PROT	Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: 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. Note=The disease is caused by mutations affecting the gene represented in this entry
SWISS-PROT	Muir-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
SWISS-PROT	Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast
SWISS-PROT	Endometrial 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
SWISS-PROT	Hereditary non-polyposis colorectal cancer 2 (HNPCC2) [MIM:609310]: 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

MLH1 cross reference
PubMed OMIM Entrez Gene NCKU SNP Nucleotide UniProt Genome Data Viewer HomoloGene