InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: MLH1

Summary

InnateDB Protein

IDBP-24602.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

MLH1

Protein Name

mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)

Synonyms

COCA2; FCC2; hMLH1; HNPCC; HNPCC2;

Species

Homo sapiens

Ensembl Protein

ENSP00000231790

InnateDB Gene

IDBG-24600 (MLH1)

Protein Structure

UniProt Annotation

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. {ECO:0000269PubMed:16873062, ECO:0000269PubMed:18206974}.

Subcellular Localization

Nucleus {ECO:0000269PubMed:11429708, ECO:0000269PubMed:14676842}.

Disease Associations

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. {ECO:0000269PubMed:10323887, ECO:0000269PubMed:10375096, ECO:0000269PubMed:10386556, ECO:0000269PubMed:10413423, ECO:0000269PubMed:10480359, ECO:0000269PubMed:10598809, ECO:0000269PubMed:10627141, ECO:0000269PubMed:10660333, ECO:0000269PubMed:10671064, ECO:0000269PubMed:10713887, ECO:0000269PubMed:10777691, ECO:0000269PubMed:10882759, ECO:0000269PubMed:11139242, ECO:0000269PubMed:11726306, ECO:0000269PubMed:11748856, ECO:0000269PubMed:11754112, ECO:0000269PubMed:11839723, ECO:0000269PubMed:11870161, ECO:0000269PubMed:12095971, ECO:0000269PubMed:12132870, ECO:0000269PubMed:12200596, ECO:0000269PubMed:12362047, ECO:0000269PubMed:12373605, ECO:0000269PubMed:12655562, ECO:0000269PubMed:12658575, ECO:0000269PubMed:14635101, ECO:0000269PubMed:14961575, ECO:0000269PubMed:15064764, ECO:0000269PubMed:15139004, ECO:0000269PubMed:15365995, ECO:0000269PubMed:15365996, ECO:0000269PubMed:16083711, ECO:0000269PubMed:16451135, ECO:0000269PubMed:17301300, ECO:0000269PubMed:17510385, ECO:0000269PubMed:18561205, ECO:0000269PubMed:7757073, ECO:0000269PubMed:8566964, ECO:0000269PubMed:8571956, ECO:0000269PubMed:8797773, ECO:0000269PubMed:8872463, ECO:0000269PubMed:8993976, ECO:0000269PubMed:9048925, ECO:0000269PubMed:9067757, ECO:0000269PubMed:9218993, ECO:0000269PubMed:9272156, ECO:0000269PubMed:9298827, ECO:0000269PubMed:9311737, ECO:0000269PubMed:9326924, ECO:0000269PubMed:9399661, ECO:0000269PubMed:9559627, ECO:0000269PubMed:9718327, ECO:0000269PubMed:9833759, ECO:0000269PubMed:9927034, ECO:0000269Ref.5}. Note=The disease is caused by mutations affecting the gene represented in this entry.Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269PubMed:17440981, ECO:0000269PubMed:7661930}. Note=The disease is caused by mutations affecting the gene represented in this entry.Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. {ECO:0000269PubMed:8751876}. Note=The disease is caused by mutations affecting the gene represented in this entry.Note=Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.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.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.

Tissue Specificity

Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 151 experimentally validated interaction(s) in this database.

Experimentally validated
Total	151 [view]
Protein-Protein	144 [view]
Protein-DNA	7 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Gene Ontology

Molecular Function

Accession	GO Term
GO:0003697	single-stranded DNA binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016887	ATPase activity
GO:0030983	mismatched DNA binding
GO:0032137	guanine/thymine mispair binding
GO:0032407	MutSalpha complex binding
GO:0043566	structure-specific DNA binding

Biological Process

GO:0000289	nuclear-transcribed mRNA poly(A) tail shortening
GO:0000712	resolution of meiotic recombination intermediates
GO:0002204	somatic recombination of immunoglobulin genes involved in immune response
GO:0006200	ATP catabolic process
GO:0006281	DNA repair
GO:0006298	mismatch repair
GO:0006303	double-strand break repair via nonhomologous end joining
GO:0006974	cellular response to DNA damage stimulus
GO:0007060	male meiosis chromosome segregation
GO:0007129	synapsis
GO:0007131	reciprocal meiotic recombination
GO:0007140	male meiosis
GO:0007283	spermatogenesis
GO:0008630	intrinsic apoptotic signaling pathway in response to DNA damage
GO:0016446	somatic hypermutation of immunoglobulin genes
GO:0016447	somatic recombination of immunoglobulin gene segments
GO:0043060	meiotic metaphase I plate congression
GO:0045132	meiotic chromosome segregation
GO:0045190	isotype switching
GO:0045950	negative regulation of mitotic recombination
GO:0048477	oogenesis
GO:0051257	spindle midzone assembly involved in meiosis

Cellular Component

GO:0000793	condensed chromosome
GO:0000794	condensed nuclear chromosome
GO:0000795	synaptonemal complex
GO:0001673	male germ cell nucleus
GO:0005634	nucleus
GO:0005694	chromosome
GO:0005712	chiasma
GO:0016020	membrane
GO:0032389	MutLalpha complex

Protein Structure and Domains

PDB ID

InterPro

IPR002099 DNA mismatch repair protein family
IPR003594 Histidine kinase-like ATPase, C-terminal domain
IPR013507 DNA mismatch repair protein, C-terminal
IPR020568 Ribosomal protein S5 domain 2-type fold

PFAM

PF02518
PF13581
PF01119

PRINTS

PIRSF

SMART

SM00387

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt

P40692