MLH1
| MLH1 | |||||||||||||||||||||||||
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| Aliases | MLH1, mutL homolog 1, COCA2, FCC2, HNPCC, HNPCC2, hMLH1 | ||||||||||||||||||||||||
| External IDs | OMIM: 120436 MGI: 101938 HomoloGene: 208 GeneCards: MLH1 | ||||||||||||||||||||||||
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| Species | Human | Mouse | |||||||||||||||||||||||
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| Location (UCSC) | n/a | Chr 9: 111.23 – 111.27 Mb | |||||||||||||||||||||||
PubMed search | [2] | [3] | |||||||||||||||||||||||
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MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) is a protein that in humans is encoded by the MLH1 gene located on Chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.
Contents
1 Function
2 Role in DNA mismatch repair
3 Deficient expression in cancer
3.1 Epigenetic repression
3.2 Deficiency in field defects
3.3 Repression in coordination with other DNA repair genes
4 Meiosis
5 Clinical significance
6 Interactions
7 See also
8 References
9 Further reading
10 External links
Function
This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). It is a human homolog of the E. coli DNA mismatch repair gene, mutL, which mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal. Defects in MLH1 are associated with the microsatellite instability (MSI) observed in HNPCC. Alternatively spliced transcript variants encoding different isoforms have been described, but their full-length natures have not been determined.[4]
Role in DNA mismatch repair
MLH1 protein is one component of a system of seven DNA mismatch repair (MMR) proteins that work coordinately in sequential steps to initiate repair of DNA mismatches in humans.[5] Defects in mismatch repair, found in about 13% of colorectal cancers, are much more frequently due to deficiency of MLH1 than deficiencies of other MMR proteins.[6] The seven MMR proteins in humans are MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2.[5] In addition, there are Exo1-dependent and Exo1-independent MMR subpathways.[7]
DNA mismatches occur where one base is improperly paired with another base, or where there is a short addition or deletion in one strand of DNA that is not matched in the other strand. Mismatches commonly occur as a result of DNA replication errors or during genetic recombination. Recognizing those mismatches and repairing them is important for cells because failure to do so results in microsatellite instability (MSI) and an elevated spontaneous mutation rate (mutator phenotype). Among 20 cancers evaluated, microsatellite instable (MSI) colon cancer (mismatch repair deficient) had the second highest frequency of mutations (after melanoma).
A heterodimer between MSH2 and MSH6 first recognizes the mismatch, although a heterodimer between MSH2 and MSH3 also can start the process. The formation of the MSH2-MSH6 heterodimer accommodates a second heterodimer of MLH1 and PMS2, although a heterodimer between MLH1 and either PMS3 or MLH3 can substitute for PMS2. This protein complex formed between the 2 sets of heterodimers enables initiation of repair of the mismatch defect.[5]
Other gene products involved in mismatch repair (subsequent to initiation by MMR genes) include DNA polymerase delta, PCNA, RPA, HMGB1, RFC and DNA ligase I, plus histone and chromatin modifying factors.[8][9]
Deficient expression in cancer
| Cancer type | Frequency of deficiency in cancer | Frequency of deficiency in adjacent field defect |
|---|---|---|
| Stomach | 32%[10][11] | 24%-28% |
| Stomach (foveolar type tumors) | 74%[12] | 71% |
| Stomach in high-incidence Kashmir Valley | 73%[13] | 20% |
| Esophageal | 73%[14] | 27% |
| Head and neck squamous cell carcinoma (HNSCC) | 31%-33%[15][16] | 20%-25% |
| Non-small cell lung cancer (NSCLC) | 69%[17] | 72% |
| Colorectal | 10%[6] |
Epigenetic repression
Only a minority of sporadic cancers with a DNA repair deficiency have a mutation in a DNA repair gene. However, a majority of sporadic cancers with a DNA repair deficiency do have one or more epigenetic alterations that reduce or silence DNA repair gene expression.[18] In the table above, the majority of deficiencies of MLH1 were due to methylation of the promoter region of the MLH1 gene. Another epigenetic mechanism reducing MLH1 expression is over-expression of miR-155.[19] MiR-155 targets MLH1 and MSH2 and an inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer.[19]
Deficiency in field defects
A field defect is an area or "field" of epithelium that has been preconditioned by epigenetic changes and/or mutations so as to predispose it towards development of cancer. As pointed out by Rubin, "The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro.[20] Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion."[21] Similarly, Vogelstein et al.[22] point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells.
In the Table above, MLH1 deficiencies were noted in the field defects (histologically normal tissues) surrounding most of the cancers. If MLH1 is epigenetically reduced or silenced, it would not likely confer a selective advantage upon a stem cell. However, reduced or absent expression of MLH1 would cause increased rates of mutation, and one or more of the mutated genes may provide the cell with a selective advantage. The expression-deficient MLH1 gene could then be carried along as a selectively neutral or only slightly deleterious passenger (hitch-hiker) gene when the mutated stem cell generates an expanded clone. The continued presence of a clone with an epigenetically repressed MLH1 would continue to generate further mutations, some of which could produce a tumor.
Repression in coordination with other DNA repair genes
In a cancer, multiple DNA repair genes are often found to be simultaneously repressed.[18] In one example, involving MLH1, Jiang et al.[23] conducted a study where they evaluated the mRNA expression of 27 DNA repair genes in 40 astrocytomas compared to normal brain tissues from non-astrocytoma individuals. Among the 27 DNA repair genes evaluated, 13 DNA repair genes, MLH1, MLH3, MGMT, NTHL1, OGG1, SMUG1, ERCC1, ERCC2, ERCC3, ERCC4, RAD50, XRCC4 and XRCC5 were all significantly down-regulated in all three grades (II, III and IV) of astrocytomas. The repression of these 13 genes in lower grade as well as in higher grade astrocytomas suggested that they may be important in early as well as in later stages of astrocytoma. In another example, Kitajima et al.[24] found that immunoreactivity for MLH1 and MGMT expression was closely correlated in 135 specimens of gastric cancer and loss of MLH1 and MGMTappeared to be synchronously accelerated during tumor progression.
Deficient expression of multiple DNA repair genes are often found in cancers,[18] and may contribute to the thousands of mutations usually found in cancers (see Mutation frequencies in cancers).
Meiosis
In addition to its role in DNA mismatch repair, MLH1 protein is also involved in meiotic crossing over.[25] MLH1 forms a heterodimer with MLH3 that appears to be necessary for oocytes to progress through metaphase II of meiosis.[26] Female and male MLH1(-/-) mutant mice are infertile, and sterility is associated with a reduced level of chiasmata.[25][27] During spermatogenesis in MLH1(-/-) mutant mice chromosomes often separate prematurely and there is frequent arrest in the first division of meiosis.[25] In humans, a common variant of the MLH1 gene is associated with increased risk of sperm damage and male infertility.[28]
A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.
MLH1 protein appears to localize to sites of crossing over in meiotic chromosomes.[25]Recombination during meiosis is often initiated by a DNA double-strand break (DSB) as illustrated in the accompanying diagram. During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination). The pathway leading to a CO involves a double Holliday junction (DHJ) intermediate. Holliday junctions need to be resolved for CO recombination to be completed.
In the budding yeast Saccharomyces cerevisiae, as in the mouse, MLH1 forms a heterodimer with MLH3. Meiotic CO requires resolution of Holliday junctions through actions of the MLH1-MLH3 heterodimer. The MLH1-MLH3 heterodimer is an endonuclease that makes single-strand breaks in supercoiled double-stranded DNA.[29][30] MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis.[29] MLH1-MLH3 heterodimer (MutL gamma) together with EXO1 and Sgs1 (ortholog of Bloom syndrome helicase) define a joint molecule resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals.[31]
Clinical significance
It can also be associated with Turcot syndrome.[32]
Interactions
MLH1 has been shown to interact with:
Bloom syndrome protein[33][34][35][36]
Exonuclease 1,[37]
MBD4,[38]
MSH4,[39]
Myc,[40] and
PMS2.[40][41][42]
See also
- Mismatch repair#MutH
References
^ abc GRCm38: Ensembl release 89: ENSMUSG00000032498 - Ensembl, May 2017
^ "Human PubMed Reference:"..mw-parser-output cite.citationfont-style:inherit.mw-parser-output .citation qquotes:"""""""'""'".mw-parser-output .citation .cs1-lock-free abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center.mw-parser-output .citation .cs1-lock-limited a,.mw-parser-output .citation .cs1-lock-registration abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center.mw-parser-output .citation .cs1-lock-subscription abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registrationcolor:#555.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration spanborder-bottom:1px dotted;cursor:help.mw-parser-output .cs1-ws-icon abackground:url("//upload.wikimedia.org/wikipedia/commons/thumb/4/4c/Wikisource-logo.svg/12px-Wikisource-logo.svg.png")no-repeat;background-position:right .1em center.mw-parser-output code.cs1-codecolor:inherit;background:inherit;border:inherit;padding:inherit.mw-parser-output .cs1-hidden-errordisplay:none;font-size:100%.mw-parser-output .cs1-visible-errorfont-size:100%.mw-parser-output .cs1-maintdisplay:none;color:#33aa33;margin-left:0.3em.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-formatfont-size:95%.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-leftpadding-left:0.2em.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-rightpadding-right:0.2em
^ "Mouse PubMed Reference:".
^ "Entrez Gene: MLH1 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)".
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^ Li GM (2014). "New insights and challenges in mismatch repair: getting over the chromatin hurdle". DNA Repair (Amst.). 19: 48–54. doi:10.1016/j.dnarep.2014.03.027. PMC 4127414. PMID 24767944.
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^ ab Mac Partlin M, Homer E, Robinson H, McCormick CJ, Crouch DH, Durant ST, Matheson EC, Hall AG, Gillespie DA, Brown R (February 2003). "Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX". Oncogene. 22 (6): 819–25. doi:10.1038/sj.onc.1206252. PMID 12584560.
^ Kondo E, Horii A, Fukushige S (April 2001). "The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2". Nucleic Acids Res. 29 (8): 1695–702. doi:10.1093/nar/29.8.1695. PMC 31313. PMID 11292842.
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Further reading
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Paraf F, Sasseville D, Watters AK, Narod S, Ginsburg O, Shibata H, Jothy S (1995). "Clinicopathological relevance of the association between gastrointestinal and sebaceous neoplasms: the Muir-Torre syndrome". Hum. Pathol. 26 (4): 422–7. doi:10.1016/0046-8177(95)90144-2. PMID 7705822.
Kolodner RD (1996). "Mismatch repair: mechanisms and relationship to cancer susceptibility". Trends Biochem. Sci. 20 (10): 397–401. doi:10.1016/S0968-0004(00)89087-8. PMID 8533151.
Peltomäki P, de la Chapelle A (1997). Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv. Cancer Res. Advances in Cancer Research. 71. pp. 93–119. doi:10.1016/S0065-230X(08)60097-4. ISBN 9780120066711. PMID 9111864.
Papadopoulos N, Lindblom A (1997). "Molecular basis of HNPCC: mutations of MMR genes". Hum. Mutat. 10 (2): 89–99. doi:10.1002/(SICI)1098-1004(1997)10:2<89::AID-HUMU1>3.0.CO;2-H. PMID 9259192.
Kauh J, Umbreit J (2004). "Colorectal cancer prevention". Current Problems in Cancer. 28 (5): 240–64. doi:10.1016/j.currproblcancer.2004.05.004. PMID 15375803.
Warusavitarne J, Schnitzler M (2007). "The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer". International Journal of Colorectal Disease. 22 (7): 739–48. doi:10.1007/s00384-006-0228-0. PMID 17109103.
Niv Y (2007). "Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer". World J. Gastroenterol. 13 (12): 1767–9. doi:10.3748/wjg.v13.i12.1767. PMC 4149951. PMID 17465465.
External links
FAQs on HNPCC from the National Institute of Health- GeneReviews/NCBI/NIH/UW entry on Lynch syndrome
MLH1+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
