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FLASH GENE
Symbol LIG4 contributors: mct/npt - updated : 15-04-2015
HGNC name ligase IV, DNA, ATP-dependent
HGNC id 6601
Corresponding disease
LIG4S LIG4 syndrome
Location 13q33.3      Physical location : 108.859.793 - 108.870.716
Synonym name
  • polydeoxyribonucleotide synthase [ATP] 4
  • polynucleotide ligase
  • sealase
  • DNA repair enzyme
  • DNA joinase
    • Synonym symbol(s) D13S870E
    EC.number 6.5.1.1
    DNA
    TYPE functioning gene
    STRUCTURE 10.93 kb     3 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 4077 - 911 - 2004 15194694
    3 splicing 3994 - 911 - 2004 15194694
    2 - 4115 - 911 - 2004 15194694
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestivepharynx   highly
    Endocrineneuroendocrinepituitary  highly
    Hearing/Equilibriumear   highly
    Lymphoid/Immunethymus    
    Reproductivemale systemtestis   
     male systemprostate   
    Respiratoryrespiratory tracttrachea   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal part, spanning &
    • 8764;600 AAs, contains DNA-binding, adenylation and oligo-binding domains, which are thought important for ligase catalytic function
  • a ligase domain
  • C-terminal fragment of LIG4 (LIG4-CT), containing two BRCT (breast cancer associated 1 C-terminal) domains without N-terminal catalytic domains and could bind to chromatin with XRCC4
    • HOMOLOGY
    interspecies homolog to murine Lig4
    Homologene
    FAMILY
  • ATP-dependent DNA ligase family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm
    basic FUNCTION
  • the ligation responsible for DNA double-strand break repair by end joining (non homologous recombination NHEJ) and V(D)J recombination
  • essential mammalian nonhomologous end joining protein used for V(D)J recombination and DNA repair (Wang 2004)
  • 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 (Karlsson 2007)
  • prevents the joining of chromatide breaks into chromosome rearrangements in BRCA1-deficient cells (Bunting 2010)
  • novel function of XRCC4 in controlling nuclear import and sub-nuclear distribution of LIG4, suggesting that XRCC4 modulates the dynamic interaction of the LIG4/XRCC4 complex with the NHEJ machinery at double-stranded DNA breaks
  • is differentially required for certain chromosome fusion events induced by telomere dysfunction-used for those owing to the overexpression of a dominant negative version of TERC2
  • LIG4 and RAD52 genes play important roles in DNA repair mechanisms
  • LIG1 is not absolutely required for cellular DNA replication and repair and either LIG3 or LIG4 can substitute for the role of LIG1 in joining Okazaki fragments
  • restoration of XRCC4 and LIG4 significantly promotes the fidelity and efficiency of NHEJ in aged fibroblasts
    • CELLULAR PROCESS nucleotide, replication
    nucleotide, repair, recombination
    PHYSIOLOGICAL PROCESS development
    text
  • neurogenesis
  • lymphogenes
    • PATHWAY
    metabolism
    signaling
    a component
  • complexing with XRCC4 and recruited by POLM to double strand break ends associated to DNA-dependent protein kinase (PRKDC)
  • plays a critical role in the repair of DNA double-strand breaks
    • INTERACTION
    DNA binding
    RNA
    small molecule nucleotide,
  • ATP binding
    • protein
  • functionally linked with ERCC4 in the repair of double-stranded DNA breaks
  • interacting with XRCC4 (XRCC4 bound to the carboxy-terminal tandem BRCT repeat of DNA ligase IV, and interaction with the second BRCT domain is necessary for stable binding to XRCC4 in cells, as well as to achieve efficient dominant-negative effects resulting in radiosensitization after ectopic overexpression of DNA LIG4 fragments in fibroblasts) (Wu 2009)
  • XRCC4 modulates the dynamic interaction of the LIG4/XRCC4 complex with the NHEJ machinery at double-stranded DNA breaks
  • DCLRE1C and LIG4 act cooperatively to promote Nonhomologous end-joining (NHEJ), thereby suppressing homologous recombination (HR) (PMI: 23967291)
  • chromatin binding of XRCC4 was dependent on the presence of LIG4
  • NHEJ1 is thought to stimulate the LIG4 activity toward incompatible or mismatched DNA ends
    • cell & other
    REGULATION
    repressed by PRKDC (negatively regulate LIG4 protein stability) (Wang 2004)
    ASSOCIATED DISORDERS
    corresponding disease(s) LIG4S
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in the bone marrow of adult myelodysplastic syndromes (Economopoulou 2010)
    tumoral     --low  
    by hypermethylation in colorectal cancer
    Susceptibility
  • multiple myeloma
  • to glioma
    • Variant & Polymorphism SNP
  • T91CT and T91TT protecting against multiple myeloma
  • SNP increasing the risk of glioma
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS