MLH3

MLH3
Identifiers
Aliases	MLH3 , HNPCC7, mutL homolog 3
External IDs	OMIM: 604395 MGI: 1353455 HomoloGene: 91153 GeneCards: MLH3
Gene location (Human)
Chr.	Chromosome 14 (human)
End	75,051,532 bp
Gene location (Mouse)
Chr.	Chromosome 12 (mouse)
End	85,317,373 bp
RNA expression pattern
	Top expressed in
	monocyte; ; Achilles tendon; ; right lobe of thyroid gland; ; left lobe of thyroid gland; ; tibial nerve; ; gastric mucosa; ; ganglionic eminence; ; anterior pituitary; ; canal of the cervix; ; right lobe of liver;
	Top expressed in
	spermatocyte; ; interventricular septum; ; ascending aorta; ; renal corpuscle; ; olfactory epithelium; ; seminiferous tubule; ; proximal tubule; ; visual cortex; ; aortic valve; ; superior frontal gyrus;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	mismatched DNA binding ; chromatin binding ; centromeric DNA binding ; single-stranded DNA binding ; protein binding ; satellite DNA binding ; ATP binding ; ATPase activity ;
Cellular component	chiasma ; male germ cell nucleus ; condensed nuclear chromosome ; mismatch repair complex ; synaptonemal complex ; nucleus ; condensed chromosome ; MutLalpha complex ;
Biological process	protein localization ; reciprocal meiotic recombination ; male meiotic nuclear division ; cellular response to DNA damage stimulus ; synaptonemal complex assembly ; DNA repair ; female meiosis I ; DNA mismatch repair ;
	Sources:Amigo / QuickGO
Orthologs
	27030
	217716
	ENSG00000119684
	ENSMUSG00000021245
	Q9UHC1
	n/a
	NM_001040108 ; NM_014381
	NM_145446 ; NM_175337 ; NM_001304475
	NP_001035197 ; NP_055196
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated October 28, 2023

DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.^[5]^[6]

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.^[6] 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.^[7] MLH3 forms a heterodimer with MLH1 that appears to be necessary for mouse oocytes to progress through metaphase II of meiosis.^[8]

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. 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.^[7] 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 a 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.^[9]^[10] MLH1-MLH3 binds specifically to Holliday junctions and may act as part of a larger complex to process Holliday junctions during meiosis.^[9] 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.^[11]

Interactions

MLH3 has been shown to interact with MSH4.^[12]

Related Research Articles

Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

Genetic recombination is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) interchromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes ; & (2) intrachromosomal recombination, occurring through crossing over.

Gene conversion is the process by which one DNA sequence replaces a homologous sequence such that the sequences become identical after the conversion event. Gene conversion can be either allelic, meaning that one allele of the same gene replaces another allele, or ectopic, meaning that one paralogous DNA sequence converts another.

DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.

A Holliday junction is a branched nucleic acid structure that contains four double-stranded arms joined. These arms may adopt one of several conformations depending on buffer salt concentrations and the sequence of nucleobases closest to the junction. The structure is named after Robin Holliday, the molecular biologist who proposed its existence in 1964.

DNA mismatch repair protein Msh2 also known as MutS homolog 2 or MSH2 is a protein that in humans is encoded by the MSH2 gene, which is located on chromosome 2. MSH2 is a tumor suppressor gene and more specifically a caretaker gene that codes for a DNA mismatch repair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to make the human MutSα mismatch repair complex. It also dimerizes with MSH3 to form the MutSβ DNA repair complex. MSH2 is involved in many different forms of DNA repair, including transcription-coupled repair, homologous recombination, and base excision repair.

DNA mismatch repair protein Mlh1 or MutL protein homolog 1 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.

MSH6 or mutS homolog 6 is a gene that codes for DNA mismatch repair protein Msh6 in the budding yeast Saccharomyces cerevisiae. It is the homologue of the human "G/T binding protein," (GTBP) also called p160 or hMSH6. The MSH6 protein is a member of the Mutator S (MutS) family of proteins that are involved in DNA damage repair.

Spo11 is a protein that in humans is encoded by the SPO11 gene. Spo11, in a complex with mTopVIB, creates double strand breaks to initiate meiotic recombination. Its active site contains a tyrosine which ligates and dissociates with DNA to promote break formation. One Spo11 protein is involved per strand of DNA, thus two Spo11 proteins are involved in each double stranded break event.

Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.

Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.

Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.

Exonuclease 1 is an enzyme that in humans is encoded by the EXO1 gene.

PMS1 protein homolog 1 is a protein that in humans is encoded by the PMS1 gene.

MutS protein homolog 5 is a protein that in humans is encoded by the MSH5 gene.

MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene.

Crossover junction endonuclease MUS81 is an enzyme that in humans is encoded by the MUS81 gene.

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

Sgs1, also known as slow growth suppressor 1, is a DNA helicase protein found in Saccharomyces cerevisiae. It is a homolog of the bacterial RecQ helicase. Like the other members of the RecQ helicase family, Sgs1 is important for DNA repair. In particular, Sgs1 collaborates with other proteins to repair double-strand breaks during homologous recombination in eukaryotes.

Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000119684 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021245 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ 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. S2CID 19733784.
1 2 "Entrez Gene: MLH3 mutL homolog 3 (E. coli)".
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: Genes, Genomes, Genetics. 3 (1): 9–22. doi:10.1534/g3.112.004622. PMC 3538346 . PMID 23316435.
↑ 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.
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.
↑ 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.
↑ 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.
↑ 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. CiteSeerX 10.1.1.586.4478 . doi:10.1093/hmg/11.15.1697. PMID 12095912.

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Kondo E, Horii A, Fukushige S (Apr 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 Research. 29 (8): 1695–702. doi:10.1093/nar/29.8.1695. PMC 31313 . PMID 11292842.
Lipkin SM, Wang V, Stoler DL, Anderson GR, Kirsch I, Hadley D, Lynch HT, Collins FS (May 2001). "Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers". Human Mutation. 17 (5): 389–96. doi: 10.1002/humu.1114 . PMID 11317354.
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 (Oct 2001). "A role for MLH3 in hereditary nonpolyposis colorectal cancer". Nature Genetics. 29 (2): 137–8. doi:10.1038/ng1001-137. PMID 11586295. S2CID 32512676.
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. CiteSeerX 10.1.1.586.4478 . doi:10.1093/hmg/11.15.1697. PMID 12095912.
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Lenzi ML, Smith J, Snowden T, Kim M, Fishel R, Poulos BK, Cohen PE (Jan 2005). "Extreme heterogeneity in the molecular events leading to the establishment of chiasmata during meiosis i in human oocytes". American Journal of Human Genetics. 76 (1): 112–27. doi:10.1086/427268. PMC 1196414 . PMID 15558497.
Cannavo E, Marra G, Sabates-Bellver J, Menigatti M, Lipkin SM, Fischer F, Cejka P, Jiricny J (Dec 2005). "Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair". Cancer Research. 65 (23): 10759–66. doi: 10.1158/0008-5472.CAN-05-2528 . PMID 16322221.
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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000119684 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021245 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10615123-5] 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. S2CID 19733784.

[entrez-6] 1 2 "Entrez Gene: MLH3 mutL homolog 3 (E. coli)".

[Brown-7] 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: Genes, Genomes, Genetics. 3 (1): 9–22. doi:10.1534/g3.112.004622. PMC 3538346 . PMID 23316435.

[pmid18057311-8] 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.

[Ranjha-9] 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.

[pmid24403070-10] 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.

[pmid22500800-11] 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.

[pmid12095912-12] 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. CiteSeerX 10.1.1.586.4478 . doi:10.1093/hmg/11.15.1697. PMID 12095912.

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