MSH4 explained
MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene.[1] [2]
Function
The MSH4 and MSH5 proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans.[3] [4] [5] In the yeast Saccharomyces cerevisiae MSH4 and MSH5 act specifically to facilitate crossovers between homologous chromosomes during meiosis. The MSH4/MSH5 complex binds and stabilizes double Holliday junctions and promotes their resolution into crossover products. An MSH4 hypomorphic (partially functional) mutant of S. cerevisiae showed a 30% genome wide reduction in crossover numbers, and a large number of meioses with non exchange chromosomes.[6] Nevertheless this mutant gave rise to spore viability patterns suggesting that segregation of non-exchange chromosomes occurred efficiently. Thus, in S. cerevisiae, proper segregation apparently does not entirely depend on crossovers between homologous pairs.
The him-14 gene of the worm Caenorhabditis elegans encodes an ortholog of MSH4.[7] Formation of crossovers during C. elegans meiosis requires the him-14(MSH4) gene. Loss of him-14(MSH-4) function severely reduces crossing over, resulting in lack of chiasmata between homologs and consequent missegregation. Thus, in C. elegans, segregation apparently does depend on crossovers between homologous pairs. Him-14(MSH4) functions during the pachytene stage of meiosis, indicating that it is not needed for establishing the preceding stages of pairing and synapsis of homologous chromosomes.
In an MSH4 mutant of rice, chiasma frequency was dramatically decreased to about 10% of the wild-type frequency, although the synaptonemal complex was normally installed.[8] It is likely that MSH4 interacts with MSH5 to promote the majority of crossovers during rice meiosis.
In general it appears that MSH4 acts during meiosis to direct the recombinational repair of some DNA double-strand breaks towards the crossover option rather than the non-cross over option (see Homologous recombination).
Interactions
MSH4 has been shown to interact with MLH1,[9] MSH5[10] and MLH3.[11]
Further reading
- Her C, Zhao N, Wu X, Tompkins JD . MutS homologues hMSH4 and hMSH5: diverse functional implications in humans . Frontiers in Bioscience . 12 . 905–11 . 2007 . 17127347 . 10.2741/2112 . free .
- Winand NJ, Panzer JA, Kolodner RD . Cloning and characterization of the human and Caenorhabditis elegans homologs of the Saccharomyces cerevisiae MSH5 gene . Genomics . 53 . 1 . 69–80 . Oct 1998 . 9787078 . 10.1006/geno.1998.5447 . free .
- Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R . hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis . Cancer Research . 59 . 4 . 816–22 . Feb 1999 . 10029069 .
- Kneitz B, Cohen PE, Avdievich E, Zhu L, Kane MF, Hou H, Kolodner RD, Kucherlapati R, Pollard JW, Edelmann W . MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice . Genes & Development . 14 . 9 . 1085–97 . May 2000 . 10.1101/gad.14.9.1085 . 10809667 . 316572 .
- Santucci-Darmanin S, Walpita D, Lespinasse F, Desnuelle C, Ashley T, Paquis-Flucklinger V . MSH4 acts in conjunction with MLH1 during mammalian meiosis . FASEB Journal . 14 . 11 . 1539–47 . Aug 2000 . 10928988 . 10.1096/fj.14.11.1539 . free .
- Räschle M, Dufner P, Marra G, Jiricny J . Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha . The Journal of Biological Chemistry . 277 . 24 . 21810–20 . Jun 2002 . 11948175 . 10.1074/jbc.M108787200 . free .
- Moens PB, Kolas NK, Tarsounas M, Marcon E, Cohen PE, Spyropoulos B . The time course and chromosomal localization of recombination-related proteins at meiosis in the mouse are compatible with models that can resolve the early DNA-DNA interactions without reciprocal recombination . Journal of Cell Science . 115 . Pt 8 . 1611–22 . Apr 2002 . 10.1242/jcs.115.8.1611 . 11950880 .
- Santucci-Darmanin S, Neyton S, Lespinasse F, Saunières A, Gaudray P, Paquis-Flucklinger V . 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 . Jul 2002 . 12095912 . 10.1093/hmg/11.15.1697 . 10.1.1.586.4478 .
- Her C, Wu X, Griswold MD, Zhou F . Human MutS homologue MSH4 physically interacts with von Hippel-Lindau tumor suppressor-binding protein 1 . Cancer Research . 63 . 4 . 865–72 . Feb 2003 . 12591739 .
- Snowden T, Acharya S, Butz C, Berardini M, Fishel R . hMSH4-hMSH5 recognizes Holliday Junctions and forms a meiosis-specific sliding clamp that embraces homologous chromosomes . Molecular Cell . 15 . 3 . 437–51 . Aug 2004 . 15304223 . 10.1016/j.molcel.2004.06.040 . free .
- Yi W, Wu X, Lee TH, Doggett NA, Her C . Two variants of MutS homolog hMSH5: prevalence in humans and effects on protein interaction . Biochemical and Biophysical Research Communications . 332 . 2 . 524–32 . Jul 2005 . 15907804 . 10.1016/j.bbrc.2005.04.154 .
- Lee TH, Yi W, Griswold MD, Zhu F, Her C . Formation of hMSH4-hMSH5 heterocomplex is a prerequisite for subsequent GPS2 recruitment . DNA Repair . 5 . 1 . 32–42 . Jan 2006 . 16122992 . 10.1016/j.dnarep.2005.07.004 .
- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
- Neyton S, Lespinasse F, Lahaye F, Staccini P, Paquis-Flucklinger V, Santucci-Darmanin S . CRM1-dependent nuclear export and dimerization with hMSH5 contribute to the regulation of hMSH4 subcellular localization . Experimental Cell Research . 313 . 17 . 3680–93 . Oct 2007 . 17869244 . 10.1016/j.yexcr.2007.08.010 .
External links
Notes and References
- Paquis-Flucklinger V, Santucci-Darmanin S, Paul R, Saunières A, Turc-Carel C, Desnuelle C . Cloning and expression analysis of a meiosis-specific MutS homolog: the human MSH4 gene . Genomics . 44 . 2 . 188–94 . Sep 1997 . 9299235 . 10.1006/geno.1997.4857 .
- Web site: Entrez Gene: MSH4 mutS homolog 4 (E. coli).
- Pochart P, Woltering D, Hollingsworth NM . Conserved properties between functionally distinct MutS homologs in yeast . J. Biol. Chem. . 272 . 48 . 30345–9 . 1997 . 9374523 . 10.1074/jbc.272.48.30345. free .
- Winand NJ, Panzer JA, Kolodner RD . Cloning and characterization of the human and Caenorhabditis elegans homologs of the Saccharomyces cerevisiae MSH5 gene . Genomics . 53 . 1 . 69–80 . 1998 . 9787078 . 10.1006/geno.1998.5447 . free .
- Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R . hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis . Cancer Res. . 59 . 4 . 816–22 . 1999 . 10029069 .
- Krishnaprasad GN, Anand MT, Lin G, Tekkedil MM, Steinmetz LM, Nishant KT . Variation in crossover frequencies perturb crossover assurance without affecting meiotic chromosome segregation in Saccharomyces cerevisiae . Genetics . 199 . 2 . 399–412 . 2015 . 25467183 . 4317650 . 10.1534/genetics.114.172320 .
- Zalevsky J, MacQueen AJ, Duffy JB, Kemphues KJ, Villeneuve AM . Crossing over during Caenorhabditis elegans meiosis requires a conserved MutS-based pathway that is partially dispensable in budding yeast . Genetics . 153 . 3 . 1271–83 . 1999 . 10.1093/genetics/153.3.1271 . 10545458 . 1460811 .
- Zhang L, Tang D, Luo Q, Chen X, Wang H, Li Y, Cheng Z . Crossover formation during rice meiosis relies on interaction of OsMSH4 and OsMSH5 . Genetics . 198 . 4 . 1447–56 . 2014 . 25278554 . 10.1534/genetics.114.168732 . 4256764.
- Santucci-Darmanin S, Walpita D, Lespinasse F, Desnuelle C, Ashley T, Paquis-Flucklinger V . MSH4 acts in conjunction with MLH1 during mammalian meiosis . FASEB Journal . 14 . 11 . 1539–47 . Aug 2000 . 10928988 . 10.1096/fj.14.11.1539 . free .
- Her C, Wu X, Griswold MD, Zhou F . Human MutS homologue MSH4 physically interacts with von Hippel-Lindau tumor suppressor-binding protein 1 . Cancer Research . 63 . 4 . 865–72 . Feb 2003 . 12591739 .
- Santucci-Darmanin S, Neyton S, Lespinasse F, Saunières A, Gaudray P, Paquis-Flucklinger V . 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 . Jul 2002 . 12095912 . 10.1093/hmg/11.15.1697 . 10.1.1.586.4478 .