MSH5 explained

MutS protein homolog 5 is a protein that in humans is encoded by the MSH5 gene.^{[1] [2] [3] [4]}

Function

This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair or meiotic recombination processes. This protein is similar to a Saccharomyces cerevisiae protein that participates in meiotic segregation fidelity and crossing-over. This protein forms heterooligomers with another member of this family, mutS homolog 4. Alternative splicing results in four transcript variants encoding three different isoforms.^[4]

Mutations

Mice homozygous for a null Msh5 mutation (Msh5-/-) are viable but sterile.^[5] In these mice, the prophase I stage of meiosis is defective due to the disruption of chromosome pairing. This meiotic failure leads, in male mice, to diminution of testicular size, and in female mice, to a complete loss of ovarian structures.

A genetic investigation was performed to test women with premature ovarian failure for mutations in each of four meiotic genes.^[6] Among 41 women with premature ovarian failure two were found to be heterozygous for a mutation in the MSH5 gene; among 34 fertile women (controls) no mutations were found in the four tested genes.

These findings in mouse and human indicate that the MSH5 protein plays an important role in meiotic recombination.

In the worm Caenorhabditis elegans, the MSH5 protein is required during meiosis both for normal spontaneous and for gamma-irradiation induced crossover recombination and chiasma formation.^[7] Meiotic recombination is often initiated by double strand breaks. MSH5 mutants retain the competence to repair DNA double-strand breaks that are present during meiosis, but they accomplish this repair in a way that does not lead to crossovers between homologous chromosomes. The known mechanism of non-crossover recombinational repair is called synthesis dependent strand annealing (see homologous recombination). MSH5 thus appears to be employed in directing the recombinational repair of some double-strand breaks towards the cross over option rather than the non-cross over option.

Interactions

MSH5 has been shown to interact with MSH4.^{[8] [9]}

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 .
• Sargent CA, Dunham I, Campbell RD . Identification of multiple HTF-island associated genes in the human major histocompatibility complex class III region . The EMBO Journal . 8 . 8 . 2305–12 . Aug 1989 . 2477242 . 401163 . 10.1002/j.1460-2075.1989.tb08357.x.
• Albertella MR, Jones H, Thomson W, Olavesen MG, Campbell RD . Localization of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II beta subunit (CSNK2B) . Genomics . 36 . 2 . 240–51 . Sep 1996 . 8812450 . 10.1006/geno.1996.0459 .
• Edelmann W, Cohen PE, Kneitz B, Winand N, Lia M, Heyer J, Kolodner R, Pollard JW, Kucherlapati R . Mammalian MutS homologue 5 is required for chromosome pairing in meiosis . Nature Genetics . 21 . 1 . 123–7 . Jan 1999 . 9916805 . 10.1038/5075 . 28944216 .
• 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 .
• Xie T, Rowen L, Aguado B, Ahearn ME, Madan A, Qin S, Campbell RD, Hood L . Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse . Genome Research . 13 . 12 . 2621–36 . Dec 2003 . 14656967 . 403804 . 10.1101/gr.1736803 .
• Anderson NL, Polanski M, Pieper R, Gatlin T, Tirumalai RS, Conrads TP, Veenstra TD, Adkins JN, Pounds JG, Fagan R, Lobley A . The human plasma proteome: a nonredundant list developed by combination of four separate sources . Molecular & Cellular Proteomics . 3 . 4 . 311–26 . Apr 2004 . 14718574 . 10.1074/mcp.M300127-MCP200 . free .
• 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 .
• Sekine H, Ferreira RC, Pan-Hammarström Q, Graham RR, Ziemba B, de Vries SS, Liu J, Hippen K, Koeuth T, Ortmann W, Iwahori A, Elliott MK, Offer S, Skon C, Du L, Novitzke J, Lee AT, Zhao N, Tompkins JD, Altshuler D, Gregersen PK, Cunningham-Rundles C, Harris RS, Her C, Nelson DL, Hammarström L, Gilkeson GS, Behrens TW . Role for Msh5 in the regulation of Ig class switch recombination . Proceedings of the National Academy of Sciences of the United States of America . 104 . 17 . 7193–8 . Apr 2007 . 17409188 . 1855370 . 10.1073/pnas.0700815104 . 2007PNAS..104.7193S . free .
• Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M . Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns . Genome Biology . 8 . 8 . R154 . 2007 . 17672918 . 2374985 . 10.1186/gb-2007-8-8-r154 . free .

Notes and References

1. Her C, Doggett NA . Cloning, structural characterization, and chromosomal localization of the human orthologue of Saccharomyces cerevisiae MSH5 gene . Genomics . 52 . 1 . 50–61 . Aug 1998 . 9740671 . 10.1006/geno.1998.5374 .
2. 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 .
3. Snowden T, Shim KS, Schmutte C, Acharya S, Fishel R . hMSH4-hMSH5 adenosine nucleotide processing and interactions with homologous recombination machinery . The Journal of Biological Chemistry . 283 . 1 . 145–54 . Jan 2008 . 17977839 . 2841433 . 10.1074/jbc.M704060200 . free .
4. Web site: Entrez Gene: MSH5 mutS homolog 5 (E. coli).
5. Edelmann W, Cohen PE, Kneitz B, Winand N, Lia M, Heyer J, Kolodner R, Pollard JW, Kucherlapati R . Mammalian MutS homologue 5 is required for chromosome pairing in meiosis . Nature Genetics . 21 . 1 . 123–7 . Jan 1999 . 9916805 . 10.1038/5075 . 28944216 .
6. Mandon-Pépin B, Touraine P, Kuttenn F, Derbois C, Rouxel A, Matsuda F, Nicolas A, Cotinot C, Fellous M . Genetic investigation of four meiotic genes in women with premature ovarian failure . European Journal of Endocrinology. 158 . 1 . 107–15 . Jan 2008 . 18166824 . 10.1530/EJE-07-0400 . free .
7. Kelly KO, Dernburg AF, Stanfield GM, Villeneuve AM . Caenorhabditis elegans msh-5 is required for both normal and radiation-induced meiotic crossing over but not for completion of meiosis . Genetics . 156 . 2 . 617–30 . Oct 2000 . 10.1093/genetics/156.2.617 . 11014811 . 1461284 .
8. 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 .
9. 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 .