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Details on Person UniProt:P40692 MLH1
| Class:Id | ReferenceGeneProduct:59369 |
|---|---|
| _chainChangeLog | initiator methionine:1 added on Fri February 6 2015;chain:2-756 added on Fri February 6 2015;initiator methionine:1 for 59369 removed on Fri Nov 03 2023;initiator methionine: for 59369 added on Fri Nov 03 2023;initiator methionine: for 59369 removed on Fri Aug 15 2025;initiator methionine:1 for 59369 added on Fri Aug 15 2025 |
| _displayName | UniProt:P40692 MLH1 |
| _timestamp | 2025-08-15 21:01:18 |
| chain | initiator methionine:1 chain:2-756 |
| checksum | C9231FC406C2CA20 |
| comment | 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-MSH3) 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 Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). 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 (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10097147). Interacts with MCM9; the interaction recruits MLH1 to chromatin (PubMed:26300262). Interacts with MCM8 (PubMed:26300262). Interacts with PMS2; this interaction promotes MLH1 stability (PubMed:11427529, PubMed:22753075, PubMed:39032648). Interacts with MBD4 (PubMed:10097147). Interacts with EXO1 (PubMed:11427529, PubMed:11429708, PubMed:12414623, PubMed:14676842, PubMed:22753075). Interacts with MTMR15/FAN1 (PubMed:20603073).INTERACTION Recruited to chromatin in a MCM9-dependent manner.ALTERNATIVE PRODUCTS Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.PTM Acetylated (PubMed:30770470). Deacetylated by HDAC6 which prevents the MutL alpha complex, formed by the MLH1-PMS2 heterodimer, from being recruited to the MutS alpha complex, formed by the MSH2-MSH6 heterodimer, leading to tolerance of DNA damage (PubMed:30770470).PTM Ubiquitinated by UBR4; leading to proteasomal degradation. This ubiquitination is counteracted by the deubiquitinase USP5.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast.DISEASE Disease susceptibility is associated with variants affecting the gene represented in this entry.DISEASE 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 Lynch syndrome but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease.DISEASE Disease susceptibility is associated with variants affecting the gene represented in this entry.SIMILARITY Belongs to the DNA mismatch repair MutL/HexB family.ONLINE INFORMATION Leiden Open Variation Database (LOVD) |
| description | recommendedName: DNA mismatch repair protein Mlh1 alternativeName: MutL protein homolog 1 |
| geneName | MLH1 COCA2 |
| identifier | P40692 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Alternative splicing ATP-binding Cell cycle Chromosome Disease variant DNA damage DNA repair Hereditary nonpolyposis colorectal cancer Nucleotide-binding Nucleus Phosphoprotein Proteomics identification Reference proteome Tumor suppressor Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 |
| name | MLH1 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:6806581] ENSEMBL:ENSG00000076242 MLH1 [Homo sapiens] |
| secondaryIdentifier | MLH1_HUMAN B4DI13 B4DQ11 E9PCU2 |
| sequenceLength | 756 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:8972018] UniProt:P40692-1 MLH1 [Homo sapiens] [ReferenceIsoform:8972019] UniProt:P40692-2 MLH1 [Homo sapiens] [ReferenceIsoform:8972020] UniProt:P40692-3 MLH1 [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:912495] MLH1 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:5444512] MLH1 H329P [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:5444526] MLH1 S252* [nucleoplasm] [Homo sapiens] |
| (referenceSequence) | [ReplacedResidue:5444514] L-histidine 329 replaced with L-proline [NonsenseMutation:5444525] Nonsense mutation at L-serine 252 |
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No pathways have been reviewed or authored by UniProt:P40692 MLH1 (59369)
