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FLASH GENE
Symbol MUS81 contributors: mct/pgu - updated : 23-01-2019
HGNC name MUS81 endonuclease homolog (S. cerevisiae)
HGNC id 29814
Location 11q13.1      Physical location : 65.627.871 - 65.633.912
Genatlas name methyl methane sulfonate (MMS), and UV-sensitive protein 81 endonuclease homolog (S. cerevisiae)
Synonym name
  • MUS81 endonuclease homolog (yeast)
  • crossover junction endonuclease MUS81
    • Synonym symbol(s) FLJ21012, FLJ44872, SLX3
    EC.number 3.1.22.-
    DNA
    TYPE functioning gene
    STRUCTURE 7.41 kb     16 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 2406 61.1 551 - 2008 1831032
    16 - 2409 - 552 - 2008 18310322
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivesalivary gland   highly
    Endocrineadrenal gland   highly
    Hearing/Equilibriumear   highly
    Lymphoid/Immunethymus   highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • helix-hairpin-helix DNA-binding domains in the N and C termini
  • a WH domain (its mutations greatly reduce binding of the isolated domain to DNA and impact on incision activity of MUS81-EME1/EME2 complexes)
  • C-terminal ERCC4 nuclease domain
    • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to yeast Mus81
    Homologene
    FAMILY
  • XPF family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus,nucleoplasm,nuclear bodies,PML
    intracellular,nucleus,nucleolus
    text
  • localizes to nucleoli and to regions of DNA damage in human S-phase cells
  • localizes to ALT-associated promyelocytic leukaemia nuclear bodies and associates with telomeric DNA in ALT cells
    • basic FUNCTION
  • playing a role in resolving Holliday junctions that arise when DNA replication is blocked by damage or by nucleotide depletion
  • playing a role in the maintenance of genomic integrity and tumor suppression
  • playing a role in the processing of stalled replication fork intermediates
  • catalyzes with EME1 coordinate bilateral cleavage of model Holliday-junction structures
  • involved in the maintenance of alternative lengthening of telomeres cell survival at least in part by homologous recombination of telomeres
  • differential functions of MUS81 and the FA pathway in repair of DNA damage during replication in human cells
  • required for the restart of stalled replication forks and for genomic integrity
  • cleaves potentially stalled replication forks, which allows dissipation of the excessive supercoiling resulting from TOP1 inhibition, and replication fork progression
  • conserved heterodimeric endonuclease MUS81-EME1 plays an important role in the maintenance of genomic integrity in eukaryotic cells
  • controlled MUS81-EME1 activity provides a safeguard mechanism to resolve DNA intermediates that may remain after replication and require processing before mitosis
  • MUS81-EME2 catalyzed cleavage of nicked and gapped duplex deoxyribonucleic acids (DNAs), generating double-strand breaks
  • the G2/M functions of MUS81, such as the cleavage of recombination intermediates and fragile site expression, are promoted by MUS81-EME1
  • MUS81 endonuclease resolves recombination intermediates and mediates cellular responses to exogenous replicative stress
  • also regulates the rate of DNA replication during normal growth by promoting replication fork progression while reducing the frequency of replication initiation events
  • MUS81 plays a key role in determining the rate of DNA replication without activating a novel group of replication origins
  • mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3
  • MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation
  • MUS81 sumoylation is important for normal mitotic chromosome congression
  • MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis
  • genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis
  • is known to limit the occurrence of chromosomal instability by processing these unresolved loci during mitosis
  • MUS81 and ERCC4 are a subset of Structure-specific endonucleases (SSEs) that resolve aberrant replication structures
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with EME1 in a structure-specific nuclease that is capable of resolving fork structures
  • MUS81-EME1 heterodimer acting as an endonuclease that exhibits a high specificity for synthetic replication fork structures, and is critical for genomic stability and the response to DNA crosslink damage and replication blockade
  • binding BTBD12
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with EME1
  • MUS81–EME1 is recruited to replication centers following DNA damage, through interaction with UHRF1
  • may cooperate with ATRX in processing of Holliday junctions intermediates that are formed during the repair of double-stranded breaks or stalled replication forks
  • interacting with FANCB (MUS81 plays an important role in cell proliferation to suppress cell death when FANCB is missing, indicating a functional linkage between MUS81 and the FA pathway)
  • interacting with CHEK1 (CHEK1-mediated protection of replication forks from MUS81/EME1 even under otherwise unchallenged conditions is therefore vital to prevent uncontrolled fork collapse and ensure proper S-phase progression in human cells)
  • WEE1 interacting with MUS81 (novel role of WEE1 in controlling MUS81 and DNA replication in human cells)
  • double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death
  • both MUS81-EME1 and MUS81-EME2 increased the activity of FEN1, but FEN1 did not stimulate the activity of MUS81-EME1/EME2
  • FBXO18 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks
  • SLX1A, like MUS81-EME1, is required for repair of DNA interstrand crosslinks, but this role appears to be independent of Holliday junctions (HJs) cleavage
  • coordinated actions of SLX1A-BTBD12 and MUS81-EME1 for Holliday junction resolution
  • GEN1 and the BTBD12-associated nucleases MUS81 and SLX1A are essential for the resolution of replication-induced Holliday junctions
  • RAD52/MUS81-dependent mechanism promoting cell viability and genome integrity in checkpoint-deficient cells, and disclose the involvement of MUS81 to multiple processes after replication stress
  • MUS81-EME2 protein, whose actions are restricted to S phase, is also responsible for telomere maintenance in telomerase-negative ALT (Alternative Lengthening of Telomeres) cells
  • MUS81 function in DNA interstrand crosslinks (ICL) repair requires interaction with SLX4
  • ATRX and MUS81 mammalian proteins physically interact and are important for the homologous recombination DNA repair pathway
  • MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting
  • RECQL5 removes RAD51 filaments stabilizing stalled replication forks at common fragile sites (CFSs) and hence facilitates CFS cleavage by MUS81-EME1
  • replication fork progression in BRCA2-deficient cells requires MUS81
  • MUS81 provides likely a mechanism of replication stress tolerance, which sustains survival of BRCA2-deficient cells
  • EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease
  • phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex
    • cell & other
    REGULATION
    Phosphorylated by CK2 kinase that phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in gastric cancer tissues
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • might be a potential marker for the malignancy of gastric cancer
    • Therapy target
    SystemTypeDisorderPubmed
    cancer  
    dual inactivation of CHEK2 and MUS81 remarkably inhibits cancer
    ANIMAL & CELL MODELS