MutS protein homolog 4 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
that in humans is encoded by the ''MSH4''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Function
The MSH4 and
MSH5 proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans.
In the yeast ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...
'' MSH4 and MSH5 act specifically to facilitate
crossovers between
homologous chromosome
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points along ...
s during
meiosis
Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately ...
.
The MSH4/MSH5 complex binds and stabilizes double
Holliday junction
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 ...
s and promotes their resolution into
crossover products. An ''MSH4''
hypomorphic
Hermann J. Muller (1890–1967), who was a 1946 Nobel Prize winner, coined the terms amorph, hypomorph, hypermorph, antimorph and neomorph to classify mutations based on their behaviour in various genetic situations, as well as gene interacti ...
(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.
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
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'' encodes an
ortholog of ''MSH4''.
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.
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
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
).
Interactions
MSH4 has been shown to
interact with
MLH1
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 ...
,
and
MLH3
DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the ''MLH3'' gene.
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 in ...
.
References
Further reading
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External links
FAQs on HNPCC{{Webarchive, url=https://web.archive.org/web/20070815221845/http://ghr.nlm.nih.gov/condition%3Dhereditarynonpolyposiscolorectalcancer , date=2007-08-15 from the
National Institute of Health
GeneReviews/NCBI/NIH/UW entry on Lynch syndrome