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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''DNA mismatch repair protein Mlh3''' is a [[protein]] that in humans is encoded by the ''MLH3'' [[gene]].<ref name="pmid10615123">{{cite journal | vauthors = Lipkin SM, Wang V, Jacoby R, Banerjee-Basu S, Baxevanis AD, Lynch HT, Elliott RM, Collins FS | title = MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability | journal = Nature Genetics | volume = 24 | issue = 1 | pages = 27–35 | date = Jan 2000 | pmid = 10615123 | pmc =  | doi = 10.1038/71643 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: MLH3 mutL homolog 3 (E. coli)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27030| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = MutL homolog 3 (E. coli)
| HGNCid = 7128
| Symbol = MLH3
| AltSymbols =; HNPCC7; MGC138372
| OMIM = 604395
| ECnumber = 
| Homologene = 79537
| MGIid = 1353455
| GeneAtlas_image1 = PBB_GE_MLH3_204838_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_MLH3_214525_x_at_tn.png
| GeneAtlas_image3 = PBB_GE_MLH3_217216_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003682 |text = chromatin binding}} {{GNF_GO|id=GO:0003696 |text = satellite DNA binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0019237 |text = centromeric DNA binding}}
| Component = {{GNF_GO|id=GO:0000793 |text = condensed chromosome}} {{GNF_GO|id=GO:0000795 |text = synaptonemal complex}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005712 |text = chiasma}}
| Process = {{GNF_GO|id=GO:0006298 |text = mismatch repair}} {{GNF_GO|id=GO:0007130 |text = synaptonemal complex assembly}} {{GNF_GO|id=GO:0007131 |text = meiotic recombination}} {{GNF_GO|id=GO:0007140 |text = male meiosis}} {{GNF_GO|id=GO:0007144 |text = female meiosis I}} {{GNF_GO|id=GO:0008104 |text = protein localization}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 27030
    | Hs_Ensembl = ENSG00000119684
    | Hs_RefseqProtein = NP_001035197
    | Hs_RefseqmRNA = NM_001040108
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 14
    | Hs_GenLoc_start = 74553239
    | Hs_GenLoc_end = 74587886
    | Hs_Uniprot = Q9UHC1
    | Mm_EntrezGene = 217716
    | Mm_Ensembl = ENSMUSG00000021245
    | Mm_RefseqmRNA = XM_900622
    | Mm_RefseqProtein = XP_905715
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 12
    | Mm_GenLoc_start = 86123632
    | Mm_GenLoc_end = 86159679
    | Mm_Uniprot = 
  }}
}}
'''MutL homolog 3 (E. coli)''', also known as '''MLH3''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: MLH3 mutL homolog 3 (E. coli)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27030| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
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.<ref name="entrez" /> Orthologs of human MLH3 have also been studied in other organisms including mouse and the budding yeast ''[[Saccharomyces cerevisiae]]''.
{{PBB_Summary
| section_title =
| summary_text = 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.<ref name="entrez">{{cite web | title = Entrez Gene: MLH3 mutL homolog 3 (E. coli)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27030| accessdate = }}</ref>
}}


==References==
==Meiosis==
{{reflist|2}}
In addition to its role in DNA mismatch repair, MLH3 protein is also involved in meiotic crossing over.<ref name=Brown>{{vcite2 journal |vauthors=Sonntag Brown M, Lim E, Chen C, Nishant KT, Alani E |title=Genetic analysis of mlh3 mutations reveals interactions between crossover promoting factors during meiosis in baker's yeast |journal=G3: Genes, Genomes, Genetics |volume=3 |issue=1 |pages=9–22 |year=2013 |pmid=23316435 |pmc=3538346 |doi=10.1534/g3.112.004622 |url=}}</ref>  MLH3 forms a [[Protein dimer|heterodimer]] with [[MLH1]] that appears to be necessary for mouse [[oocyte]]s to progress through metaphase II of [[meiosis]].<ref name="pmid18057311">{{vcite2 journal |vauthors=Kan R, Sun X, Kolas NK, Avdievich E, Kneitz B, Edelmann W, Cohen PE |title=Comparative analysis of meiotic progression in female mice bearing mutations in genes of the DNA mismatch repair pathway |journal=Biol. Reprod. |volume=78 |issue=3 |pages=462–71 |year=2008 |pmid=18057311 |doi=10.1095/biolreprod.107.065771 |url=}}</ref>
==Further reading==
 
[[File:Homologous Recombination.jpg|thumb|400px|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.<ref name=Brown /> [[Genetic recombination|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 [[DNA supercoil|supercoiled]] double-stranded DNA.<ref name=Ranjha>{{vcite2 journal |vauthors=Ranjha L, Anand R, Cejka P |title=The Saccharomyces cerevisiae Mlh1-Mlh3 heterodimer is an endonuclease that preferentially binds to Holliday junctions |journal=J. Biol. Chem. |volume=289 |issue=9 |pages=5674–86 |year=2014 |pmid=24443562 |pmc=3937642 |doi=10.1074/jbc.M113.533810 |url=}}</ref><ref name="pmid24403070">{{vcite2 journal |vauthors=Rogacheva MV, Manhart CM, Chen C, Guarne A, Surtees J, Alani E |title=Mlh1-Mlh3, a meiotic crossover and DNA mismatch repair factor, is a Msh2-Msh3-stimulated endonuclease |journal=J. Biol. Chem. |volume=289 |issue=9 |pages=5664–73 |year=2014 |pmid=24403070 |pmc=3937641 |doi=10.1074/jbc.M113.534644 |url=}}</ref>  MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during [[meiosis]].<ref name=Ranjha />  MLH1-MLH3 heterodimer (MutL gamma) together with [[Exo1]] and [[Sgs1]] (ortholog of [[Bloom syndrome protein|Bloom syndrome helicase]]) define a joint molecule resolution pathway that produces the majority of crossovers in budding yeast and, by inference, in mammals.<ref name="pmid22500800">{{vcite2 journal |vauthors=Zakharyevich K, Tang S, Ma Y, Hunter N |title=Delineation of joint molecule resolution pathways in meiosis identifies a crossover-specific resolvase |journal=Cell |volume=149 |issue=2 |pages=334–47 |year=2012 |pmid=22500800 |pmc=3377385 |doi=10.1016/j.cell.2012.03.023 |url=}}</ref>
 
== Interactions ==
 
MLH3 has been shown to [[Protein-protein interaction|interact]] with [[MSH4]].<ref name=pmid12095912>{{cite journal | vauthors = Santucci-Darmanin S, Neyton S, Lespinasse F, Saunières A, Gaudray P, Paquis-Flucklinger V | title = The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination | journal = Human Molecular Genetics | volume = 11 | issue = 15 | pages = 1697–706 | date = Jul 2002 | pmid = 12095912 | doi = 10.1093/hmg/11.15.1697 }}</ref>
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH | title = Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease | journal = Nature | volume = 375 | issue = 6534 | pages = 754–60 | date = Jun 1995 | pmid = 7596406 | doi = 10.1038/375754a0 }}
| citations =
* {{cite journal | vauthors = Kondo E, Horii A, Fukushige S | title = The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2 | journal = Nucleic Acids Research | volume = 29 | issue = 8 | pages = 1695–702 | date = Apr 2001 | pmid = 11292842 | pmc = 31313 | doi = 10.1093/nar/29.8.1695 }}
*{{cite journal | author=Sherrington R, Rogaev EI, Liang Y, ''et al.'' |title=Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. |journal=Nature |volume=375 |issue= 6534 |pages= 754-60 |year= 1995 |pmid= 7596406 |doi= 10.1038/375754a0 }}
* {{cite journal | vauthors = Lipkin SM, Wang V, Stoler DL, Anderson GR, Kirsch I, Hadley D, Lynch HT, Collins FS | title = Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers | journal = Human Mutation | volume = 17 | issue = 5 | pages = 389–96 | date = May 2001 | pmid = 11317354 | doi = 10.1002/humu.1114 }}
*{{cite journal | author=Lipkin SM, Wang V, Jacoby R, ''et al.'' |title=MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. |journal=Nat. Genet. |volume=24 |issue= 1 |pages= 27-35 |year= 2000 |pmid= 10615123 |doi= 10.1038/71643 }}
* {{cite journal | vauthors = Wu Y, Berends MJ, Sijmons RH, Mensink RG, Verlind E, Kooi KA, van der Sluis T, Kempinga C, van dDer Zee AG, Hollema H, Buys CH, Kleibeuker JH, Hofstra RM | title = A role for MLH3 in hereditary nonpolyposis colorectal cancer | journal = Nature Genetics | volume = 29 | issue = 2 | pages = 137–8 | date = Oct 2001 | pmid = 11586295 | doi = 10.1038/ng1001-137 }}
*{{cite journal  | author=Kondo E, Horii A, Fukushige S |title=The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. |journal=Nucleic Acids Res. |volume=29 |issue= 8 |pages= 1695-702 |year= 2001 |pmid= 11292842 |doi= }}
* {{cite journal | vauthors = Santucci-Darmanin S, Neyton S, Lespinasse F, Saunières A, Gaudray P, Paquis-Flucklinger V | title = The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination | journal = Human Molecular Genetics | volume = 11 | issue = 15 | pages = 1697–706 | date = Jul 2002 | pmid = 12095912 | doi = 10.1093/hmg/11.15.1697 }}
*{{cite journal | author=Lipkin SM, Wang V, Stoler DL, ''et al.'' |title=Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers. |journal=Hum. Mutat. |volume=17 |issue= 5 |pages= 389-96 |year= 2001 |pmid= 11317354 |doi= 10.1002/humu.1114 }}
* {{cite journal | vauthors = Hienonen T, Laiho P, Salovaara R, Mecklin JP, Järvinen H, Sistonen P, Peltomäki P, Lehtonen R, Nupponen NN, Launonen V, Karhu A, Aaltonen LA | title = Little evidence for involvement of MLH3 in colorectal cancer predisposition | journal = International Journal of Cancer | volume = 106 | issue = 2 | pages = 292–6 | date = Aug 2003 | pmid = 12800209 | doi = 10.1002/ijc.11218 }}
*{{cite journal | author=Wu Y, Berends MJ, Sijmons RH, ''et al.'' |title=A role for MLH3 in hereditary nonpolyposis colorectal cancer. |journal=Nat. Genet. |volume=29 |issue= 2 |pages= 137-8 |year= 2001 |pmid= 11586295 |doi= 10.1038/ng1001-137 }}
* {{cite journal | vauthors = Lenzi ML, Smith J, Snowden T, Kim M, Fishel R, Poulos BK, Cohen PE | title = Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes | journal = American Journal of Human Genetics | volume = 76 | issue = 1 | pages = 112–27 | date = Jan 2005 | pmid = 15558497 | pmc = 1196414 | doi = 10.1086/427268 }}
*{{cite journal | author=Santucci-Darmanin S, Neyton S, Lespinasse F, ''et al.'' |title=The DNA mismatch-repair MLH3 protein interacts with MSH4 in meiotic cells, supporting a role for this MutL homolog in mammalian meiotic recombination. |journal=Hum. Mol. Genet. |volume=11 |issue= 15 |pages= 1697-706 |year= 2003 |pmid= 12095912 |doi=  }}
* {{cite journal | vauthors = Cannavo E, Marra G, Sabates-Bellver J, Menigatti M, Lipkin SM, Fischer F, Cejka P, Jiricny J | title = Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair | journal = Cancer Research | volume = 65 | issue = 23 | pages = 10759–66 | date = Dec 2005 | pmid = 16322221 | doi = 10.1158/0008-5472.CAN-05-2528 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S | title = Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes | journal = Genome Research | volume = 16 | issue = 1 | pages = 55–65 | date = Jan 2006 | pmid = 16344560 | pmc = 1356129 | doi = 10.1101/gr.4039406 }}
*{{cite journal | author=Hienonen T, Laiho P, Salovaara R, ''et al.'' |title=Little evidence for involvement of MLH3 in colorectal cancer predisposition. |journal=Int. J. Cancer |volume=106 |issue= 2 |pages= 292-6 |year= 2003 |pmid= 12800209 |doi= 10.1002/ijc.11218 }}
* {{cite journal | vauthors = Taylor NP, Powell MA, Gibb RK, Rader JS, Huettner PC, Thibodeau SN, Mutch DG, Goodfellow PJ | title = MLH3 mutation in endometrial cancer | journal = Cancer Research | volume = 66 | issue = 15 | pages = 7502–8 | date = Aug 2006 | pmid = 16885347 | doi = 10.1158/0008-5472.CAN-06-0248 }}
*{{cite journal | author=Lenzi ML, Smith J, Snowden T, ''et al.'' |title=Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes. |journal=Am. J. Hum. Genet. |volume=76 |issue= 1 |pages= 112-27 |year= 2005 |pmid= 15558497 |doi= 10.1086/427268 }}
* {{cite journal | vauthors = Liu HX, Li Y, Jiang XD, Yin HN, Zhang L, Wang Y, Yang J | title = Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer | journal = World Journal of Gastroenterology | volume = 12 | issue = 33 | pages = 5281–6 | date = Sep 2006 | pmid = 16981255 | doi = 10.3748/wjg.v12.i33.5281 }}
*{{cite journal | author=Cannavo E, Marra G, Sabates-Bellver J, ''et al.'' |title=Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair. |journal=Cancer Res. |volume=65 |issue= 23 |pages= 10759-66 |year= 2006 |pmid= 16322221 |doi= 10.1158/0008-5472.CAN-05-2528 }}
* {{cite journal | vauthors = Korhonen MK, Raevaara TE, Lohi H, Nyström M | title = Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC | journal = Oncology Reports | volume = 17 | issue = 2 | pages = 351–4 | date = Feb 2007 | pmid = 17203173 | doi = 10.3892/or.17.2.351 }}
*{{cite journal | author=Kimura K, Wakamatsu A, Suzuki Y, ''et al.'' |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55-65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 }}
* {{cite journal | vauthors = Erdeniz N, Nguyen M, Deschênes SM, Liskay RM | title = Mutations affecting a putative MutLalpha endonuclease motif impact multiple mismatch repair functions | journal = DNA Repair | volume = 6 | issue = 10 | pages = 1463–70 | date = Oct 2007 | pmid = 17567544 | pmc = 2366940 | doi = 10.1016/j.dnarep.2007.04.013 }}
*{{cite journal | author=Taylor NP, Powell MA, Gibb RK, ''et al.'' |title=MLH3 mutation in endometrial cancer. |journal=Cancer Res. |volume=66 |issue= 15 |pages= 7502-8 |year= 2006 |pmid= 16885347 |doi= 10.1158/0008-5472.CAN-06-0248 }}
*{{cite journal | author=Liu HX, Li Y, Jiang XD, ''et al.'' |title=Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer. |journal=World J. Gastroenterol. |volume=12 |issue= 33 |pages= 5281-6 |year= 2007 |pmid= 16981255 |doi= }}
*{{cite journal | author=Korhonen MK, Raevaara TE, Lohi H, Nyström M |title=Conditional nuclear localization of hMLH3 suggests a minor activity in mismatch repair and supports its role as a low-risk gene in HNPCC. |journal=Oncol. Rep. |volume=17 |issue= 2 |pages= 351-4 |year= 2007 |pmid= 17203173 |doi= }}
*{{cite journal | author=Erdeniz N, Nguyen M, Deschênes SM, Liskay RM |title=Mutations affecting a putative MutLalpha endonuclease motif impact multiple mismatch repair functions. |journal=DNA Repair (Amst.) |volume=6 |issue= 10 |pages= 1463-70 |year= 2007 |pmid= 17567544 |doi= 10.1016/j.dnarep.2007.04.013 }}
}}
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Latest revision as of 18:29, 4 December 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

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]

File:Homologous Recombination.jpg
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. ↑ 2.0 2.1 "Entrez Gene: MLH3 mutL homolog 3 (E. coli)".
  3. ↑ 3.0 3.1 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: Genes, Genomes, Genetics. 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. ↑ 5.0 5.1 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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