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LIG4 DNA ligase 4 [ Homo sapiens (human) ]

Gene ID: 3981, updated on 8-Dec-2020

Summary

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Official Symbol
LIG4provided by HGNC
Official Full Name
DNA ligase 4provided by HGNC
Primary source
HGNC:HGNC:6601
See related
Ensembl:ENSG00000174405 MIM:601837
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
LIG4S
Summary
The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
Expression
Ubiquitous expression in brain (RPKM 5.8), testis (RPKM 4.8) and 25 other tissues See more
Orthologs
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Genomic context

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See LIG4 in Genome Data Viewer
Location:
13q33.3
Exon count:
6
Annotation release Status Assembly Chr Location
109.20201120 current GRCh38.p13 (GCF_000001405.39) 13 NC_000013.11 (108207442..108218349, complement)
105 previous assembly GRCh37.p13 (GCF_000001405.25) 13 NC_000013.10 (108859790..108870716, complement)

Chromosome 13 - NC_000013.11Genomic Context describing neighboring genes Neighboring gene family with sequence similarity 155 member A Neighboring gene uncharacterized LOC107984581 Neighboring gene FAM155A intronic transcript 1 Neighboring gene uncharacterized LOC112268111 Neighboring gene Sharpr-MPRA regulatory region 13792 Neighboring gene abhydrolase domain containing 13 Neighboring gene TNF superfamily member 13b Neighboring gene RNA, 5S ribosomal pseudogene 39

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. [Cytogenetic, kariopathological and morphological abnormalities of spermatozoa and urothelial cells in human granulocytic anaplasmosis depending on polymorphism of the gene of DNA ligase IV]. Ilyinskikh NN, et al. Urologiia, 2019 Apr. PMID 31184023
  2. A Novel Missense LIG4 Mutation in a Patient With a Phenotype Mimicking Behçet's Disease. Taskiran EZ, et al. J Clin Immunol, 2019 Jan. PMID 30617623
  3. Structures of DNA-bound human ligase IV catalytic core reveal insights into substrate binding and catalysis. Kaminski AM, et al. Nat Commun, 2018 Jul 6. PMID 29980672, Free PMC Article
  4. Mutagenic repair of double-stranded DNA breaks in vaccinia virus genomes requires cellular DNA ligase IV activity in the cytosol. Luteijn RD, et al. J Gen Virol, 2018 Jun. PMID 29676720
  5. Polymorphisms of DNA repair genes XRCC1 and LIG4 and idiopathic male infertility. Ghasemi H, et al. Syst Biol Reprod Med, 2017 Dec. PMID 28991497

See all (183) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Complex genetic interactions between DNA polymerase beta and the NHEJ ligase.
    Title: Complex genetic interactions between DNA polymerase β and the NHEJ ligase.
  2. Downregulation of LIG4 was consistently associated with de novo myelodysplastic syndrome .
    Title: Can synthetic lethality approach be used with DNA repair genes for primary and secondary MDS?
  3. Our research revealed XRCC6 C1310G and LIG4 T9I polymorphisms are associated with diminished risk of colorectal cancer. However, to confirm obtained results, a further investigations should be carried out.
    Title: Association of XRCC6 C1310G and LIG4 T9I polymorphisms of NHEJ DNA repair pathway with risk of colorectal cancer in the Polish population.
  4. The phenotypical spectrum of LIG4 deficiency.
    Title: A Novel Missense LIG4 Mutation in a Patient With a Phenotype Mimicking Behçet's Disease.
  5. Study indicated that miR-1246 suppressed LIG4 expression by directly binding to its 3'-UTR inducing genomic DNA damage and reduced cell proliferation.
    Title: Exosome-packaged miR-1246 contributes to bystander DNA damage by targeting LIG4.
  6. The genetic polymorphism of the effects of human granulocytic anaplasmosis was revealed, and the most significant cytogenetical damage was found in the patients carrying the Ile/Ile genotype of the LIG4 Thr9Ile gene.
    Title: [Cytogenetic, kariopathological and morphological abnormalities of spermatozoa and urothelial cells in human granulocytic anaplasmosis depending on polymorphism of the gene of DNA ligase IV].
  7. Disrupting the NAD+ recognition site in the BRCT domain(BRCA1 C-terminal domain) impairs non-homologous end joining (NHEJ) in cell. Taken together, our study reveals that in addition to ATP, Ligase IV may use NAD+ as an alternative adenylation donor for NHEJ repair and maintaining genomic stability.
    Title: Human DNA ligase IV is able to use NAD+ as an alternative adenylation donor for DNA ends ligation.
  8. Our data show that DNA ligase IV can act outside of the nucleus to allow repair of dsDNA breaks in poxvirus genomes.
    Title: Mutagenic repair of double-stranded DNA breaks in vaccinia virus genomes requires cellular DNA ligase IV activity in the cytosol.
  9. Cells doubly deficient in Pol theta; and Lig4 exhibit 100% gene-targeting efficiency because of virtually no random integration events.
    Title: Dual loss of human POLQ and LIG4 abolishes random integration.
  10. These studies provide a scaffold for defining impacts of LigIV catalytic core mutations and deficiencies in human LIG4 syndrome.
    Title: Structures of DNA-bound human ligase IV catalytic core reveal insights into substrate binding and catalysis.
Submit: New GeneRIF Correction See all GeneRIFs (90)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description Tests
Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study.
GeneReviews: Not available
Lig4 syndrome
MedGen: C1847827 OMIM: 606593 GeneReviews: Not available
Compare labs
Multiple myeloma
MedGen: C0026764 OMIM: 254500 GeneReviews: Not available
Compare labs

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
ATP binding IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
DNA binding IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
DNA binding IDA
Inferred from Direct Assay
more info
 PubMed 
DNA ligase (ATP) activity IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
DNA ligase (ATP) activity IDA
Inferred from Direct Assay
more info
 PubMed 
DNA ligase activity IDA
Inferred from Direct Assay
more info
 PubMed 
DNA ligase activity TAS
Traceable Author Statement
more info
  
ligase activity IDA
Inferred from Direct Assay
more info
 PubMed 
metal ion binding IEA
Inferred from Electronic Annotation
more info
  
protein C-terminus binding IPI
Inferred from Physical Interaction
more info
 PubMed 
protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
DNA biosynthetic process IEA
Inferred from Electronic Annotation
more info
  
DNA ligation IDA
Inferred from Direct Assay
more info
 PubMed 
DNA ligation involved in DNA recombination ISS
Inferred from Sequence or Structural Similarity
more info
  
DNA ligation involved in DNA repair IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
DNA ligation involved in DNA repair IDA
Inferred from Direct Assay
more info
 PubMed 
DNA ligation involved in DNA repair ISS
Inferred from Sequence or Structural Similarity
more info
  
DNA replication IEA
Inferred from Electronic Annotation
more info
  
T cell differentiation in thymus ISS
Inferred from Sequence or Structural Similarity
more info
  
T cell receptor V(D)J recombination ISS
Inferred from Sequence or Structural Similarity
more info
  
V(D)J recombination IDA
Inferred from Direct Assay
more info
 PubMed 
cell cycle IEA
Inferred from Electronic Annotation
more info
  
cell division IEA
Inferred from Electronic Annotation
more info
  
cell population proliferation ISS
Inferred from Sequence or Structural Similarity
more info
  
cellular response to ionizing radiation IGI
Inferred from Genetic Interaction
more info
 PubMed 
cellular response to lithium ion IEA
Inferred from Electronic Annotation
more info
  
central nervous system development ISS
Inferred from Sequence or Structural Similarity
more info
  
chromosome organization ISS
Inferred from Sequence or Structural Similarity
more info
  
double-strand break repair IDA
Inferred from Direct Assay
more info
 PubMed 
double-strand break repair ISS
Inferred from Sequence or Structural Similarity
more info
  
double-strand break repair via classical nonhomologous end joining IMP
Inferred from Mutant Phenotype
more info
 PubMed 
double-strand break repair via nonhomologous end joining IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
double-strand break repair via nonhomologous end joining IDA
Inferred from Direct Assay
more info
 PubMed 
double-strand break repair via nonhomologous end joining IGI
Inferred from Genetic Interaction
more info
 PubMed 
double-strand break repair via nonhomologous end joining IMP
Inferred from Mutant Phenotype
more info
 PubMed 
double-strand break repair via nonhomologous end joining ISS
Inferred from Sequence or Structural Similarity
more info
  
double-strand break repair via nonhomologous end joining TAS
Traceable Author Statement
more info
  
establishment of integrated proviral latency TAS
Traceable Author Statement
more info
  
immunoglobulin V(D)J recombination IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
in utero embryonic development ISS
Inferred from Sequence or Structural Similarity
more info
  
isotype switching ISS
Inferred from Sequence or Structural Similarity
more info
  
negative regulation of neuron apoptotic process ISS
Inferred from Sequence or Structural Similarity
more info
  
neuron apoptotic process ISS
Inferred from Sequence or Structural Similarity
more info
  
nucleotide-excision repair, DNA gap filling IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
nucleotide-excision repair, DNA gap filling IDA
Inferred from Direct Assay
more info
 PubMed 
positive regulation of chromosome organization IMP
Inferred from Mutant Phenotype
more info
 PubMed 
positive regulation of fibroblast proliferation ISS
Inferred from Sequence or Structural Similarity
more info
  
positive regulation of neurogenesis ISS
Inferred from Sequence or Structural Similarity
more info
  
pro-B cell differentiation ISS
Inferred from Sequence or Structural Similarity
more info
  
response to X-ray IMP
Inferred from Mutant Phenotype
more info
 PubMed 
response to gamma radiation ISS
Inferred from Sequence or Structural Similarity
more info
  
single strand break repair IDA
Inferred from Direct Assay
more info
 PubMed 
somatic stem cell population maintenance ISS
Inferred from Sequence or Structural Similarity
more info
  
Component Evidence Code Pubs
DNA ligase IV complex IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
DNA ligase IV complex IMP
Inferred from Mutant Phenotype
more info
 PubMed 
DNA-dependent protein kinase-DNA ligase 4 complex IBA
Inferred from Biological aspect of Ancestor
more info
 PubMed 
DNA-dependent protein kinase-DNA ligase 4 complex IDA
Inferred from Direct Assay
more info
 PubMed 
DNA-dependent protein kinase-DNA ligase 4 complex ISS
Inferred from Sequence or Structural Similarity
more info
  
chromosome, telomeric region IC
Inferred by Curator
more info
 PubMed 
condensed chromosome IDA
Inferred from Direct Assay
more info
 PubMed 
cytoplasmic ribonucleoprotein granule IDA
Inferred from Direct Assay
more info
  
nonhomologous end joining complex IDA
Inferred from Direct Assay
more info
 PubMed 
nucleoplasm IDA
Inferred from Direct Assay
more info
  
nucleoplasm TAS
Traceable Author Statement
more info
  
nucleus IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
DNA ligase 4
Names
DNA joinase
DNA ligase IV
DNA repair enzyme
ligase IV, DNA, ATP-dependent
polydeoxyribonucleotide synthase [ATP] 4
polynucleotide ligase
sealase
NP_001091738.1
NP_001317524.1
NP_001339527.1
NP_001339528.1
NP_001339529.1
NP_001339530.1
NP_001339531.1
NP_001339532.1
NP_001339533.1
NP_001366024.1
NP_002303.2
NP_996820.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_007396.1 RefSeqGene

    Range
    2167..13093
    Download
    GenBank, FASTA, Sequence Viewer (Graphics), LRG_79

mRNA and Protein(s)

  1. NM_001098268.2 → NP_001091738.1  DNA ligase 4 isoform 1

    See identical proteins and their annotated locations for NP_001091738.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) differs in the 5' UTR, compared to variant 1. Variants 1-3 and 5-10 all encode the same isoform (1).
    Source sequence(s)
    BC037491, BX648833
    Consensus CDS
    CCDS9508.1
    UniProtKB/Swiss-Prot
    P49917
    UniProtKB/TrEMBL
    A0A024RE06
    Related
    ENSP00000385955.1, ENST00000405925.2
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  2. NM_001330595.2 → NP_001317524.1  DNA ligase 4 isoform 2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) differs in the 5' UTR, lacks a portion of the 5' coding region, and initiates translation at a dowstream start codon, compared to variant 1. The encoded isoform (2) has a shorter N-terminus than isoform 1.
    Source sequence(s)
    AK292419, AL157762, BC037491, BX648833, DC372305
    Consensus CDS
    CCDS81779.1
    UniProtKB/Swiss-Prot
    P49917
    UniProtKB/TrEMBL
    A0A0C4DGV9, A8K8Q4
    Related
    ENSP00000480814.1, ENST00000614526.1

  3. NM_001352598.2 → NP_001339527.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5), as well as variants 1-3 and 6-10, encodes isoform 1.
    Source sequence(s)
    AL157762
    Consensus CDS
    CCDS9508.1
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  4. NM_001352599.2 → NP_001339528.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (6), as well as variants 1-3, 5, and 7-10, encodes isoform 1.
    Source sequence(s)
    AL157762
    Consensus CDS
    CCDS9508.1
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  5. NM_001352600.2 → NP_001339529.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (7), as well as variants 1-3, 5, 6, and 8-10, encodes isoform 1.
    Source sequence(s)
    AL157762
    Consensus CDS
    CCDS9508.1
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  6. NM_001352601.2 → NP_001339530.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (8), as well as variants 1-3, 5-7, 9, and 10, encodes isoform 1.
    Source sequence(s)
    AL157762
    Consensus CDS
    CCDS9508.1
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  7. NM_001352602.2 → NP_001339531.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (9), as well as variants 1-3, 5-8, and 10, encodes isoform 1.
    Source sequence(s)
    AL157762
    Consensus CDS
    CCDS9508.1
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  8. NM_001352603.1 → NP_001339532.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (10), as well as variants 1-3 and 5-9, encodes isoform 1.
    Source sequence(s)
    AL157762
    Consensus CDS
    CCDS9508.1
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  9. NM_001352604.2 → NP_001339533.1  DNA ligase 4 isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (11) encodes the longest isoform (3).
    Source sequence(s)
    AL157762
    Conserved Domains (3) summary
    TIGR00574
    Location:93 → 614
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:668 → 742
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:762 → 795
    DNA_ligase_IV; DNA ligase IV

  10. NM_001379095.1 → NP_001366024.1  DNA ligase 4 isoform 1

    Status: REVIEWED

    Source sequence(s)
    AL157762, DA211056
    Related
    ENSP00000484288.1, ENST00000611712.4

  11. NM_002312.3 → NP_002303.2  DNA ligase 4 isoform 1

    See identical proteins and their annotated locations for NP_002303.2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1), as well as variants 2, 3, and 5-10, encodes isoform 1.
    Source sequence(s)
    AI809944, BC037491, CD102896, X83441
    Consensus CDS
    CCDS9508.1
    UniProtKB/Swiss-Prot
    P49917
    UniProtKB/TrEMBL
    A0A024RE06
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

  12. NM_206937.2 → NP_996820.1  DNA ligase 4 isoform 1

    See identical proteins and their annotated locations for NP_996820.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) differs in the 5' UTR, compared to variant 1. Variants 1-3 and 5-10 all encode the same isoform (1).
    Source sequence(s)
    AL157762, BC037491, BX648833
    Consensus CDS
    CCDS9508.1
    UniProtKB/Swiss-Prot
    P49917
    UniProtKB/TrEMBL
    A0A024RE06
    Related
    ENSP00000402030.1, ENST00000442234.5
    Conserved Domains (3) summary
    TIGR00574
    Location:81 → 602
    dnl1; DNA ligase I, ATP-dependent (dnl1)
    pfam00533
    Location:656 → 730
    BRCT; BRCA1 C Terminus (BRCT) domain
    pfam11411
    Location:750 → 783
    DNA_ligase_IV; DNA ligase IV

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20201120

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

  1. NC_000013.11 Reference GRCh38.p13 Primary Assembly

    Range
    108207442..108218349 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)
Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P49917.2 GenPept UniProtKB/Swiss-Prot:P49917

Gene LinkOut

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