MLH3

MutL homolog 3
Identifiers
Symbols MLH3 ; HNPCC7
External IDs OMIM: 604395 MGI: 1353455 HomoloGene: 91153 GeneCards: MLH3 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 27030 217716
Ensembl ENSG00000119684 ENSMUSG00000021245
UniProt Q9UHC1 Q68FG1
RefSeq (mRNA) NM_001040108 NM_001304475
RefSeq (protein) NP_001035197 NP_001291404
Location (UCSC) Chr 14:
75.01 – 75.05 Mb		 Chr 12:
85.23 – 85.27 Mb
PubMed search

DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.[1][2]

Function

This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined.[2] Orthologs of human MLH3 have also been studied in other organisms including mouse and the budding yeast Saccharomyces cerevisiae.

Meiosis

In addition to its role in DNA mismatch repair, MLH3 protein is also involved in meiotic crossing over.[3] MLH3 forms a heterodimer with MLH1 that appears to be necessary for mouse oocytes to progress through metaphase II of meiosis.[4]

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.

The MLH1-MLH3 heterodimers promote crossovers.[3] 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, MLH3 forms a heterodimer with MLH1. 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.[5][6] MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis.[5] 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.[7]

Interactions

MLH3 has been shown to interact with MSH4.[8]

References

  1. ↑ Lipkin SM, Wang V, Jacoby R, Banerjee-Basu S, Baxevanis AD, Lynch HT, Elliott RM, Collins FS (Jan 2000). "MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability". Nature Genetics 24 (1): 27–35. doi:10.1038/71643. PMID 10615123.
  2. 1 2 "Entrez Gene: MLH3 mutL homolog 3 (E. coli)".
  3. 1 2 Sonntag Brown M, Lim E, Chen C, Nishant KT, Alani E (2013). "Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast". G3 (Bethesda) 3 (1): 9–22. doi:10.1534/g3.112.004622. PMC 3538346. PMID 23316435.
  4. ↑ Kan R, Sun X, Kolas NK, Avdievich E, Kneitz B, Edelmann W, et al. (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.
  5. 1 2 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Santucci-Darmanin S, Neyton S, Lespinasse F, Saunières A, Gaudray P, Paquis-Flucklinger V (Jul 2002). "The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination". Human Molecular Genetics 11 (15): 1697–706. doi:10.1093/hmg/11.15.1697. PMID 12095912.

Further reading

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