DNA mismatch repair protein Mlh1; mutL protein homolog 1 (MLH1, COCA2)
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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
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:
- 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
More general terms
Component of
References
- ↑ UniProt http://www.uniprot.org/uniprot/P40692.html
- ↑ Hereditary non-polyposis colorectal cancer db http://www.nfdht.nl/
- ↑ Atlas of Genetics & Cytogenetics in Oncology & Haematology http://atlasgeneticsoncology.org/genes/MLH1ID149ch3p21.html
- ↑ GeneReviews http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/MLH1
- ↑ NIEHS-SNPs http://egp.gs.washington.edu/data/mlh1/
- ↑ Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397-401. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8533151
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4292
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4292
- OMIM: https://mirror.omim.org/entry/120436
- OMIM: https://mirror.omim.org/entry/158320
- OMIM: https://mirror.omim.org/entry/276300
- OMIM: https://mirror.omim.org/entry/608089
- OMIM: https://mirror.omim.org/entry/609310
- UniProt: http://www.uniprot.org/uniprot/P40692.html