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FLASH GENE
Symbol XRCC4 contributors: mct/pgu - updated : 21-03-2016
HGNC name X-ray repair complementing defective repair in Chinese hamster cells 4
HGNC id 12831
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal part, spanning 200 AAs, forms globular domain and coiled-coil domain, the latter of which mediates dimerization of XRCC4 and its interaction with LIG4
  • C-terminal part of XRCC4, spanning 130 AAs, forming a globular structure at the opposite of N-terminal globular head domain
  • mono polymer homomer , heteromer , dimer , tetramer
    HOMOLOGY
    interspecies homolog to murine Xrcc4 (76.1pc)
    Homologene
    FAMILY
  • XRCC4 family
  • CATEGORY DNA associated
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus
    basic FUNCTION
  • involved in DNA double-strand break repair by end joining (non homologous recombination) and V(D)J recombination
  • controlling processing of DNA for nonhomologous end-joining
  • may play a role in the age at diagnosis and risk of breast cancer in non-BRCA1/2, heritable breast cancer cases
  • DNA Ligase IV/XRCC4 recruited by PRKDC to DNA double-strand breaks prevents the formation of long single strand-DNA ends at double-strand breaks during the S phase
  • may serve as a flexible tether between XRCC5 and LIG4
  • XRCC5/XRCC4 pathway is conservative and can accomodate non-fully complementary ends at the cost of limited mutagenesis
  • LIG4/XRCC4 complex is responsible for NHEJ ligation step and XRCC4 enhances the joining activity of LIG4
  • its phosphorylation and complexation have subtle effects on PNKP activity and reveal new potential roles for XRCC4 and PNKP in NHEJ (nonhomologous end joining)
  • one function for XRCC4 is the displacement of PNKP from processed strand break termini, and the second is the recruitment of DNA ligase IV to seal the breaks after PNKP processing of the termini
  • XRCC4 and NHEJ1 filaments are suitable to align DNA molecules and function to facilitate LIG4 end joining required for DSB repair
  • is required not only for the promotion of NHEJ during interphase but also for its M-phase-specific suppression of DSB repair
  • XRCC4 and NHEJ1 are two structurally related proteins that function in DNA double-strand break (DSB) repair
  • plays a critical role in non-homologous end-joining DNA repair
  • restoration of XRCC4 and LIG4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts
  • CELLULAR PROCESS nucleotide, repair
    PHYSIOLOGICAL PROCESS development
    text lymphogenesis, neurogenesis
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with DNA ligase IV (LIG4) and recruited by POLM to double strand break ends associated to DNA-dependent protein kinase (PRKDC)
  • homodimer or heterotetramer
  • INTERACTION
    DNA binding
    RNA
    small molecule
    protein
  • interacting with NHEJ1
  • interacting directly with XRCC5 (Mari 2006)
  • interacting directly with PRKDC
  • interacting with XLF, APTX, APLF
  • unphosphorylated XRCC4 interacts with PNKP through a lower affinity interaction site within the catalytic domain and this interaction stimulates the turnover of PNKP
  • interaction between NHEJ1 and XRCC4 is mediated via head-to-head interactions and in the XLF/XRCC4/BRCT complex, alternating repeating units of XLF and XRCC4/BRCT place the BRCT domain on one side of the filament
  • XRCC4 and NHEJ1 interactions promotes alignment of long DNA substrates to facilitate ligation
  • XRCC4 modulates the dynamic interaction of the LIG4/XRCC4 complex with the NHEJ machinery at double-stranded DNA breaks
  • XRCC4 interacts with NHEJ1, and XRCC4 and NHEJ1 form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair
  • chromatin binding of XRCC4 was dependent on the presence of LIG4
  • XRCC2 and XRCC4, were transcriptionally activated by ZNF281 through a DNA-binding-dependent mechanism
  • cell & other
    REGULATION
    Other SUMO modification regulates its localization and function in DNA double-strand break repair
    phosphorylated by PRKDC
    phosphorylation by CK2 promotes interaction with APTX
    monoubiquitinated
    ASSOCIATED DISORDERS
    corresponding disease(s) MOPD5
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in synovial sarcoma after SYT-SSX fusion
    Susceptibility
  • to myeloma for some htSNPs
  • to glioma
  • to endometriosis
  • Variant & Polymorphism SNP , other
  • increasing the risk of multiple myeloma
  • increasing the risk of glioma
  • XRCC4 G-1394T is a significant SNP in bladder carcinogenesis
  • XRCC4 codon 247*A and XRCC4 promoter -1394*T related genotypes and alleles, but not XRCC4 intron 3 I/D polymorphism, might be associated with endometriosis
  • XRCC4 G-1394T may be responsible for lung carcinogenesis
  • significant association between XRCC4 genotypes with NSCLC risk
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS