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DNA mismatch repair protein Mlh1; mutL protein homolog 1 (MLH1, COCA2)

Function: - DNA mismatch repair endodeoxyribonuclease - heterodimerizes with PMS2 to form mutL alpha - component of the post-replicative DNA mismatch repair system - 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 & PCNA is sufficient to activate endonuclease activity of PMS2 - introduces single-strand breaks near the mismatch & thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch - DNA methylation would prevent cleavage & 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 & can lead to apoptosis in case of major DNA damages - heterodimerizes with MLH3 to form mutL gamma which plays a role in meiosis heterodimer of MLH1 & PMS2 (mutL alpha), MLH1 & PMS1 (mutL beta) or MLH1 & 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); this association could be a dynamic process changing throughout the cell cycle & within subnuclear domains - interacts with MBD4. interacts with EXO1 Structure: - belongs to the DNA mismatch repair mutL/hexB family Compartment: nucleus Expression: - expressed in colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder & heart Pathology: - defects in MLH1 are the cause of hereditary non-polyposis colorectal cancer type 2 - defects in MLH1 are a cause of: a) mismatch repair cancer syndrome (Turcot syndrome) b) Muir-Torre syndrome c) susceptibility to endometrial cancer - defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast Notes: - 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 do not have identifiable mutations in MLH1, even though it is silenced, that an epimutation can phenocopy a genetic disease

Interactions

molecular events

Related

MLH1 gene

General

mutL/PMS1 family protein nuclear protein phosphoprotein

Properties

SIZE: entity length = 756 aa MW = 85 kD MOTIF: EXO1 interaction {410-650} MOTIF: Ser phosphorylation site {S477} binding site EFFECTOR-BOUND: Mismatch repair endonuclease PMS2

Database Correlations

OMIM correlations MORBIDMAP 120436 UniProt P40692 PFAM correlations Entrez Gene 4292 Kegg hsa:4292

References

  1. UniProt :accession P40692
  2. Hereditary non-polyposis colorectal cancer db http://www.nfdht.nl/
  3. Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/MLH1ID149ch3p21.html
  4. GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/MLH1
  5. NIEHS-SNPs http://egp.gs.washington.edu/data/mlh1/
  6. Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397-401. Review. PMID: 8533151

Component-of

BRCA1-associated genome surveillance complex (BASC)