From Wikipedia, the free encyclopedia
Jump to: navigation, search
MutL homolog 1
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols MLH1 ; COCA2; FCC2; HNPCC; HNPCC2; hMLH1
External IDs OMIM120436 MGI101938 HomoloGene208 GeneCards: MLH1 Gene
RNA expression pattern
PBB GE MLH1 202520 s at tn.png
More reference expression data
Species Human Mouse
Entrez 4292 17350
Ensembl ENSG00000076242 ENSMUSG00000032498
UniProt P40692 Q9JK91
RefSeq (mRNA) NM_000249 NM_026810
RefSeq (protein) NP_000240 NP_081086
Location (UCSC) Chr 3:
36.99 – 37.05 Mb
Chr 9:
111.23 – 111.27 Mb
PubMed search [1] [2]

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 MLH11 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.


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.[1]


In addition to its role in DNA mismatch repair, MLH1 protein is also involved in meiotic crossing over.[2] MLH1 forms a heterodimer with MLH3 that appears to be necessary for oocytes to progress through metaphase II of meiosis.[3] Female and male MLH1(-/-) mutant mice are infertile, and sterility is associated with a reduced level of chiasmata.[2][4] During spermatogenesis in MLH1(-/-) mutant mice chromosomes often separate prematurely and there is frequent arrest in the first division of meiosis.[2] In humans, a common variant of the MLH1 gene is associated with increased risk of sperm damage and male infertility.[5]

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.[2] 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.[6][7] MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis.[6] 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.[8]

Clinical significance[edit]

It can also be associated with Turcot syndrome.[9]


MLH1 has been shown to interact with:

See also[edit]


  1. ^ "Entrez Gene: MLH1 mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli)". 
  2. ^ a b c d Baker SM, Plug AW, Prolla TA, Bronner CE, Harris AC, Yao X, Christie DM, Monell C, Arnheim N, Bradley A, Ashley T, Liskay RM (1996). "Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over". Nat. Genet. 13 (3): 336–42. doi:10.1038/ng0796-336. PMID 8673133. 
  3. ^ Kan R, Sun X, Kolas NK, Avdievich E, Kneitz B, Edelmann W, Cohen PE (2008). "Comparative analysis of meiotic progression in female mice bearing mutations in genes of the DNA mismatch repair pathway". Biol. Reprod. 78 (3): 462–71. doi:10.1095/biolreprod.107.065771. PMID 18057311. 
  4. ^ Wei K, Kucherlapati R, Edelmann W (2002). "Mouse models for human DNA mismatch-repair gene defects". Trends Mol Med 8 (7): 346–53. doi:10.1016/s1471-4914(02)02359-6. PMID 12114115. 
  5. ^ Ji G, Long Y, Zhou Y, Huang C, Gu A, Wang X (2012). "Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility". BMC Med 10: 49. doi:10.1186/1741-7015-10-49. PMC 3378460. PMID 22594646. 
  6. ^ a b Ranjha L, Anand R, Cejka P (2014). "The Saccharomyces cerevisiae Mlh1-Mlh3 heterodimer is an endonuclease that preferentially binds to Holliday junctions". J. Biol. Chem. 289 (9): 5674–86. doi:10.1074/jbc.M113.533810. PMC 3937642. PMID 24443562. 
  7. ^ Rogacheva MV, Manhart CM, Chen C, Guarne A, Surtees J, Alani E (2014). "Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease". J. Biol. Chem. 289 (9): 5664–73. doi:10.1074/jbc.M113.534644. PMC 3937641. PMID 24403070. 
  8. ^ Zakharyevich K, Tang S, Ma Y, Hunter N (2012). "Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase". Cell 149 (2): 334–47. doi:10.1016/j.cell.2012.03.023. PMC 3377385. PMID 22500800. 
  9. ^ Lebrun C, Olschwang S, Jeannin S, Vandenbos F, Sobol H, Frenay M (2007). "Turcot syndrome confirmed with molecular analysis". Eur. J. Neurol. 14 (4): 470–2. doi:10.1111/j.1468-1331.2006.01669.x. PMID 17389002. 
  10. ^ Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. PMC 316544. PMID 10783165. 
  11. ^ Langland G, Kordich J, Creaney J, Goss KH, Lillard-Wetherell K, Bebenek K, Kunkel TA, Groden J (August 2001). "The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair". J. Biol. Chem. 276 (32): 30031–5. doi:10.1074/jbc.M009664200. PMID 11325959. 
  12. ^ Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (August 2001). "Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha". Nucleic Acids Res. 29 (15): 3172–80. doi:10.1093/nar/29.15.3172. PMC 55826. PMID 11470874. 
  13. ^ Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I (November 2001). "Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1". Nucleic Acids Res. 29 (21): 4378–86. doi:10.1093/nar/29.21.4378. PMC 60193. PMID 11691925. 
  14. ^ Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R (August 2001). "The interaction of DNA mismatch repair proteins with human exonuclease I". J. Biol. Chem. 276 (35): 33011–8. doi:10.1074/jbc.M102670200. PMID 11427529. 
  15. ^ Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung AT, Matsumoto Y, Golemis EA, Genuardi M, Neri G (March 1999). "MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1". Proc. Natl. Acad. Sci. U.S.A. 96 (7): 3969–74. doi:10.1073/pnas.96.7.3969. PMC 22404. PMID 10097147. 
  16. ^ Santucci-Darmanin S, Walpita D, Lespinasse F, Desnuelle C, Ashley T, Paquis-Flucklinger V (August 2000). "MSH4 acts in conjunction with MLH1 during mammalian meiosis". FASEB J. 14 (11): 1539–47. doi:10.1096/fj.14.11.1539. PMID 10928988. 
  17. ^ a b 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. 
  18. ^ 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. 
  19. ^ Guerrette S, Acharya S, Fishel R (March 1999). "The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer". J. Biol. Chem. 274 (10): 6336–41. doi:10.1074/jbc.274.10.6336. PMID 10037723. 

Further reading[edit]

External links[edit]