MUS81

Last updated
MUS81
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MUS81 , SLX3, MUS81 structure-specific endonuclease subunit
External IDs OMIM: 606591; MGI: 1918961; HomoloGene: 5725; GeneCards: MUS81; OMA:MUS81 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_025128
NM_001350283

NM_027877

RefSeq (protein)

NP_079404
NP_001337212

NP_082153

Location (UCSC) Chr 11: 65.86 – 65.87 Mb Chr 19: 5.53 – 5.54 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Crossover junction endonuclease MUS81 is an enzyme that in humans is encoded by the MUS81 gene. [5] [6] [7]

Contents

In mammalian somatic cells, MUS81 and another structure specific DNA endonuclease, XPF (ERCC4), play overlapping and essential roles in completion of homologous recombination. [8] The significant overlap in function between these enzymes is most likely related to processing joint molecules such as D-loops and nicked Holliday junctions. [8]

Meiosis

MUS81 is a component of a minor chromosomal crossover (CO) pathway in the meiosis of budding yeast, plants and vertebrates. [9] However, in the protozoan Tetrahymena thermophila, MUS81 appears to be part of an essential (if not the predominant) CO pathway. [9] The MUS81 pathway also appears to be the predominant CO pathway in the fission yeast Schizosaccharomyces pombe . [9]

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 relationship of the CO pathway to the overall process of meiotic recombination is illustrated in the accompanying diagram. Recombination during meiosis is often initiated by a DNA double-strand break (DSB). 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 "invades" the DNA of an 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.

MUS81-MMS4, in the budding yeast Saccharomyces cerevisiae , is a DNA structure-selective endonuclease that cleaves joint DNA molecules formed during homologous recombination in meiosis and mitosis. [10] The MUS81-MMS4 endonuclease, although a minor resolvase for CO formation in S. cerevisiae, is crucial for limiting chromosome entanglements by suppressing multiple consecutive recombination events from initiating from the same DSB. [11]

Mus81 deficient mice have significant meiotic defects including the failure to repair a subset of DSBs. [12]

Interactions

MUS81 has been shown to interact with CHEK2. [5]

Related Research Articles

<span class="mw-page-title-main">Chromosomal crossover</span> Cellular process

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.

<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

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.

<span class="mw-page-title-main">Heteroduplex</span>

A heteroduplex is a double-stranded (duplex) molecule of nucleic acid originated through the genetic recombination of single complementary strands derived from different sources, such as from different homologous chromosomes or even from different organisms.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

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.

<span class="mw-page-title-main">Holliday junction</span> Branched nucleic acid structure

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.

Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand genetic linkage because it is the only source of recombination within an individual. Additionally, mitotic recombination can result in the expression of recessive alleles in an otherwise heterozygous individual. This expression has important implications for the study of tumorigenesis and lethal recessive alleles. Mitotic homologous recombination occurs mainly between sister chromatids subsequent to replication. Inter-sister homologous recombination is ordinarily genetically silent. During mitosis the incidence of recombination between non-sister homologous chromatids is only about 1% of that between sister chromatids.

<span class="mw-page-title-main">Sister chromatid exchange</span>

Sister chromatid exchange (SCE) is the exchange of genetic material between two identical sister chromatids.

<span class="mw-page-title-main">MLH1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Spo11</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Exonuclease 1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">MSH4</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">MLH3</span> Protein-coding gene in the species Homo sapiens

DNA mismatch repair protein Mlh3 is a protein that in humans is encoded by the MLH3 gene.

<span class="mw-page-title-main">EME1</span> Protein-coding gene in the species Homo sapiens

Crossover junction endonuclease EME1 is an enzyme that in humans is encoded by the EME1 gene. It forms a complex with MUS81 which resolves Holliday junctions. In mammalian cells the EME1/MUS81 protein complex is redundant for DNA damage repair with GEN1 endonuclease. In mice, EME1/MUS81 and GEN1 redundantly contribute to Holliday junction processing. When homozygous mutations of Gen1 and Eme1 were combined in mice the result was synthetic lethality at an early embryonic stage. Homozygosity for Gen1 mutations did not cause a DNA repair deficiency in mice. But when mice were both homozygous mutant for Gen1 and also heterozyous for an Emc1 mutation, they showed increased sensitivity to DNA damaging agents. This finding, indicated a redundant role of GEN1 and EME1 in DNA repair. Gen1 and Emc1 were also shown to have redundant roles in meiotic recombination.

<span class="mw-page-title-main">RMI1</span> Protein-coding gene in the species Homo sapiens

RecQ-mediated genome instability protein 1 is a protein that in humans is encoded by the RMI1 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.

<span class="mw-page-title-main">Meiotic recombination checkpoint</span>

The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.

<span class="mw-page-title-main">Synthesis-dependent strand annealing</span>

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.

Crossover junction endodeoxyribonuclease, also known as Holliday junction resolvase, Holliday junction endonuclease, Holliday junction-cleaving endonuclease, Holliday junction-resolving endoribonuclease, crossover junction endoribonuclease, and cruciform-cutting endonuclease, is an enzyme involved in DNA repair and homologous recombination. Specifically, it performs endonucleolytic cleavage that results in single-stranded crossover between two homologous DNA molecules at the Holliday junction to produce recombinant DNA products for chromosomal segregation. This process is known as Holliday junction resolution.

<span class="mw-page-title-main">GEN1, Holliday junction 5' flap endonuclease</span> Protein-coding gene in the species Homo sapiens

GEN1, Holliday junction 5' flap endonuclease is a protein that in humans is encoded by the GEN1 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000172732 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024906 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.
  5. 1 2 Chen XB, Melchionna R, Denis CM, Gaillard PH, Blasina A, Van de Weyer I, Boddy MN, Russell P, Vialard J, McGowan CH (Nov 2001). "Human Mus81-associated endonuclease cleaves Holliday junctions in vitro". Molecular Cell. 8 (5): 1117–27. doi: 10.1016/S1097-2765(01)00375-6 . PMID   11741546.
  6. Constantinou A, Chen XB, McGowan CH, West SC (Oct 2002). "Holliday junction resolution in human cells: two junction endonucleases with distinct substrate specificities". The EMBO Journal. 21 (20): 5577–85. doi:10.1093/emboj/cdf554. PMC   129086 . PMID   12374758.
  7. "Entrez Gene: MUS81 MUS81 endonuclease homolog (S. cerevisiae)".
  8. 1 2 Kikuchi K, Narita T, Pham VT, Iijima J, Hirota K, Keka IS, Mohiuddin, Okawa K, Hori T, Fukagawa T, Essers J, Kanaar R, Whitby MC, Sugasawa K, Taniguchi Y, Kitagawa K, Takeda S (2013). "Structure-specific endonucleases xpf and mus81 play overlapping but essential roles in DNA repair by homologous recombination". Cancer Res. 73 (14): 4362–71. doi:10.1158/0008-5472.CAN-12-3154. PMC   3718858 . PMID   23576554.
  9. 1 2 3 Lukaszewicz A, Howard-Till RA, Loidl J (2013). "Mus81 nuclease and Sgs1 helicase are essential for meiotic recombination in a protist lacking a synaptonemal complex". Nucleic Acids Res. 41 (20): 9296–309. doi:10.1093/nar/gkt703. PMC   3814389 . PMID   23935123.
  10. Mukherjee S, Wright WD, Ehmsen KT, Heyer WD (2014). "The Mus81-Mms4 structure-selective endonuclease requires nicked DNA junctions to undergo conformational changes and bend its DNA substrates for cleavage". Nucleic Acids Res. 42 (10): 6511–22. doi:10.1093/nar/gku265. PMC   4041439 . PMID   24744239.
  11. Oke A, Anderson CM, Yam P, Fung JC (2014). "Controlling meiotic recombinational repair - specifying the roles of ZMMs, Sgs1 and Mus81/Mms4 in crossover formation". PLOS Genet. 10 (10): e1004690. doi: 10.1371/journal.pgen.1004690 . PMC   4199502 . PMID   25329811.
  12. Holloway JK, Booth J, Edelmann W, McGowan CH, Cohen PE (2008). "MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis". PLOS Genet. 4 (9): e1000186. doi: 10.1371/journal.pgen.1000186 . PMC   2525838 . PMID   18787696.

Further reading