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| Aliases | MSH4 , mutS homolog 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 602105 MGI: 1860077 HomoloGene: 1830 GeneCards: MSH4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene. [5] [6]
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| Aliases | MSH4 , mutS homolog 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 602105 MGI: 1860077 HomoloGene: 1830 GeneCards: MSH4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene. [5] [6]
The MSH4 and MSH5 proteins form a hetero-oligomeric structure (heterodimer) in yeast and humans. [7] [8] [9] In the yeast Saccharomyces cerevisiae MSH4 and MSH5 act specifically to facilitate crossovers between homologous chromosomes during meiosis. [7] 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. [10] 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. [11] 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. [12] 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).
MSH4 has been shown to interact with MLH1, [13] MSH5 [8] [9] [14] and MLH3. [15]
Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, the sperm or egg cells. It involves two rounds of division that ultimately result in four cells, each with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a zygote, a cell with two copies of each chromosome again.
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.
Synapsis or Syzygy is the pairing of two chromosomes that occurs during meiosis. It allows matching-up of homologous pairs prior to their segregation, and possible chromosomal crossover between them. Synapsis takes place during prophase I of meiosis. When homologous chromosomes synapse, their ends are first attached to the nuclear envelope. These end-membrane complexes then migrate, assisted by the extranuclear cytoskeleton, until matching ends have been paired. Then the intervening regions of the chromosome are brought together, and may be connected by a protein-DNA complex called the synaptonemal complex. During synapsis, autosomes are held together by the synaptonemal complex along their whole length, whereas for sex chromosomes, this only takes place at one end of each chromosome.
Zygotene is the second stage of prophase I during meiosis, the specialized cell division that reduces the chromosome number by half to produce haploid gametes. It follows the leptotene stage.
The pachytene stage, also known as pachynema, is the third stage of prophase I during meiosis, the specialized cell division that reduces chromosome number by half to produce haploid gametes. It follows the zygotene stage.
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.
Sister chromatid exchange (SCE) is the exchange of genetic material between two identical sister chromatids.
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. The gene is 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.
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.
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.
Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene.
Crossover junction endonuclease MUS81 is an enzyme that in humans is encoded by the MUS81 gene.
DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.
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.
The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.
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.
Abby F. Dernburg is a professor of Cell and Developmental Biology at the University of California, Berkeley, an Investigator of the Howard Hughes Medical Institute, and a Faculty Senior Scientist at Lawrence Berkeley National Laboratory.