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FLASH GENE
Symbol SLX4 contributors: mct/npt/pgu - updated : 23-12-2016
HGNC name SLX4 structure-specific endonuclease subunit
HGNC id 23845
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
15 - 7304 - 1834 - 2009 19596235
EXPRESSION
Type restricted
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Lymphoid/Immunelymph node   lowly
Nervousbrain   lowly
 spinal cord   lowly
Reproductivemale systemtestis  lowly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Blood / hematopoieticbone marrow    Homo sapiens
Nervousperipherous   
cells
SystemCellPubmedSpeciesStageRna symbol
Reproductivespermatocyte Homo sapiens
Reproductivespermatogonia Homo sapiens
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal region containing a ubiquitin-binding zinc finger (UBZ) domain, required for interstrand cross-links processing, and for interaction with monoubiquitylated FANCD2
  • BTB/POZ domain
  • HOMOLOGY
    interspecies ortholog to murine Btbd12
    ortholog to D. melanogaster MUS312.
    Homologene
    FAMILY
  • SLX4 family
  • CATEGORY DNA associated
    SUBCELLULAR LOCALIZATION
    text
  • localizes to pre-meiotic spermatogonia and to meiotic spermatocytes in wildtype males
  • basic FUNCTION
  • ATM/ATR checkpoint kinase substrate, displaying robust Holliday junction resolvase activity in addition to 5 prime flap endonuclease activity
  • important for the cells ability to respond to DNA
  • interstrand crosslinks and protein-DNA adducts
  • acts as a docking platform for multiple structure-specific endonucleases
  • with GIYD1 have important functions in the maintenance of genome integrity and in the tolerance to DNA damage inflicted by an alkylating agent
  • scaffold for DNA repair nucleases ERCC4-ERCC1, MUS81-EME1, and GIYD1
  • regulator of structure-specific nucleases and with GIYD1 are important regulators of genome stability in human cells
  • assembles a modular toolkit for repair of specific types of DNA lesions and is critical for cellular responses to replication fork failure
  • coordinates three separate endonucleases, and recently recognized as an important regulator of DNA repair
  • mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination
  • requirement to interact with the structure-specific endonuclease ERCC4-ERCC1 to promote crosslink repair
  • play an essential role in cell proliferation, probably by promoting the resolution of interchromatid homologous recombination intermediates
  • plays a key role in the repair of spontaneous DNA damage
  • plays a key role as an interacting platform for enzymes involved in the processing of HR intermediates and is also linked to the repair of interstrand cross-link, a process coordinated by the FA pathway
  • functions throughout gametogenesis to maintain genome stability, possibly by co-ordinating repair processes and/or by linking DNA repair events to the cell cycle via ATM
  • has a crucial role in preventing excessive RAD9A-dependent activation of CHEK2 (23160493)
  • MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    essential component to the FA-BRCA genome maintenance pathway
    a component
  • forms a multiprotein complex with the ERCC4-ERCC1, MUS81-EME1, and SLX1A endonucleases and also associates with MSH2/MSH3 mismatch repair complex, telomere binding complex TERF2-TERF2IP(RAP1), the protein kinase PLK1 and the uncharacterized protein C20orf94
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binds the XPF(ERCC4) and MUS81 subunits of the XPF-ERCC1 and MUS81-EME1 endonucleases and is required for DNA interstrand crosslink repair
  • GIYD1-BTBD12 module promotes symmetrical cleavage of static and migrating Holliday junctions (HJs), identifying GIYD1-BTBD12 as a HJ resolvase
  • interacts with the RAD1-RAD10 endonuclease to control cleavage of 3 prime flaps during repair of double-strand breaks (DSBs)
  • recruited to sites of DNA damage by monoubiquitylated FANCD2, and this recruitment requires its UBZ domain
  • could potentially interact with ubiquitylated FANCD2 or PCNA
  • has potentially a role in specifically blocking CHEK2 hyperactivation
  • 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
  • MUS81 function in DNA interstrand crosslinks (ICL) repair requires interaction with SLX4
  • BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis
  • MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting
  • phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) FANCP
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Btbd12 knockout mice recapitulate many key features associated with human Fanconi anemia, including the development of blood cytopenias and diverse developmental defect
  • Btbd12 mutant mice exhibit increased genomic instability in the form of elevated blood cell micronucleus formation similar to that seen in Atm(-/-) males