LIG4 DNA ligase 4 [Homo sapiens (human)] - Gene

Summary

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: mouse all

Genomic context

Location:: 13q33.3

Exon count:: 6

Annotation release	Status	Assembly	Chr	Location
109.20190905	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_000013.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
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].
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.
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.
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.
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.
study demonstrated that there was an association between DNA ligase 4 Thr9Ile polymorphism and male infertility and suggests CT genotype as a risk factor for male infertility
Title: Polymorphisms of DNA repair genes XRCC1 and LIG4 and idiopathic male infertility.
An increased frequency of binucleated lymphocytes with micronuclei was increased in carriers of the T/T genotype of the LIG4 (rs1805388) gene compared to miners harbouring the C/T genotype.
Title: Association of DNA repair gene polymorphisms with genotoxic stress in underground coal miners.
Cellular NHEJ of diverse ends thus identifies the steps necessary for repair through LIG4-mediated sensing of differences in end structure and consequent dynamic remodeling of aligned ends.
Title: DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining.
This study shown that both ligase IV and XRCC4 may act in concert to modulate the development of glioma.
Title: Genetic effects of XRCC4 and ligase IV genes on human glioma.

Submit: New GeneRIF Correction See all GeneRIFs (86)

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
Lig4 syndrome MedGen: C1847827 OMIM: 606593 GeneReviews: Not available	Compare labs
Multiple myeloma MedGen: C0026764 OMIM: 254500 GeneReviews: Not available	Compare labs

NHGRI GWAS Catalog

Description
Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study. NHGRI GWA Catalog NHGRI GWA CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Pathways from BioSystems

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2-LTR circle formation, organism-specific biosystem (from REACTOME)
2-LTR circle formation, organism-specific biosystemThe formation of 2-LTR circles requires the action of the cellular non-homologous DNA end-joining pathway. Specifically the cellular Ku, XRCC4 and ligase IV proteins are needed. Evidence for this i...
DNA Double-Strand Break Repair, organism-specific biosystem (from REACTOME)
DNA Double-Strand Break Repair, organism-specific biosystemNumerous types of DNA damage can occur within a cell due to the endogenous production of oxygen free radicals, normal alkylation reactions, or exposure to exogenous radiations and chemicals. Double-s...
DNA Repair, organism-specific biosystem (from REACTOME)
DNA Repair, organism-specific biosystemDNA repair is a phenomenal multi-enzyme, multi-pathway system required to ensure the integrity of the cellular genome. Living organisms are constantly exposed to harmful metabolic by-products, enviro...
Disease, organism-specific biosystem (from REACTOME)
Disease, organism-specific biosystemBiological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular ...
Early Phase of HIV Life Cycle, organism-specific biosystem (from REACTOME)
Early Phase of HIV Life Cycle, organism-specific biosystemIn the early phase of HIV lifecycle, an active virion binds and enters a target cell mainly by specific interactions of the viral envelope proteins with host cell surface receptors. The virion core...
HIV Infection, organism-specific biosystem (from REACTOME)
HIV Infection, organism-specific biosystemThe global pandemic of Human Immunodeficiency Virus (HIV) infection has resulted in tens of millions of people infected by the virus and millions more affected. UNAIDS estimates around 40 million ...
HIV Life Cycle, organism-specific biosystem (from REACTOME)
HIV Life Cycle, organism-specific biosystemThe life cycle of HIV-1 is divided into early and late phases, shown schematically in the figure. In the early phase, an HIV-1 virion binds to receptors and co-receptors on the human host cell surfac...
Infectious disease, organism-specific biosystem (from REACTOME)
Infectious disease, organism-specific biosystem
Infectious disease
Integration of provirus, organism-specific biosystem (from REACTOME)
Integration of provirus, organism-specific biosystemFor retroviral DNA to direct production of progeny virions it must become covalently integrated into the host cell chromosome (reviewed in Coffin et al. 1997; Hansen et al. 1998). Analyses of mutants...
Non-homologous end-joining, organism-specific biosystem (from KEGG)
Non-homologous end-joining, organism-specific biosystemNonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) by direct ligation. NHEJ involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (MRX c...
Non-homologous end-joining, conserved biosystem (from KEGG)
Non-homologous end-joining, conserved biosystemNonhomologous end joining (NHEJ) eliminates DNA double-strand breaks (DSBs) by direct ligation. NHEJ involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (MRX c...
Nonhomologous End-Joining (NHEJ), organism-specific biosystem (from REACTOME)
Nonhomologous End-Joining (NHEJ), organism-specific biosystemThe nonhomologous end joining (NHEJ) pathway is initiated in response to the formation of DNA double-strand breaks (DSBs) induced by DNA-damaging agents, such as ionizing radiation. DNA DSBs are reco...

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

LIG4 (e-PCR)
- UniSTS:505382

G67234 (e-PCR)
- UniSTS:186438

SGC35475 (e-PCR)
- UniSTS:70806

RH98317 (e-PCR)
- UniSTS:85669

LIG4_354 (e-PCR)
- UniSTS:277452

D13S1452 (e-PCR)
- UniSTS:60382

D13S870E (e-PCR)
- UniSTS:151532

Homology

Homologs of the LIG4 gene: The LIG4 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, S.cerevisiae, K.lactis, E.gossypii, S.pombe, M.oryzae, N.crassa, A.thaliana, and frog.
Orthologs from Annotation Pipeline: 296 organisms have orthologs with human gene LIG4
Orthologs

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 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
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
nuclear chromosome, telomeric region	IC Inferred by Curator 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

EC 6.5.1.1

NP_001317524.1

EC 6.5.1.1

NP_001339527.1

EC 6.5.1.1

NP_001339528.1

EC 6.5.1.1

NP_001339529.1

EC 6.5.1.1

NP_001339530.1

EC 6.5.1.1

NP_001339531.1

EC 6.5.1.1

NP_001339532.1

EC 6.5.1.1

NP_001339533.1

EC 6.5.1.1

NP_002303.2

EC 6.5.1.1

NP_996820.1

EC 6.5.1.1

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

NG_007396.1 RefSeqGene

Range

2167..13093

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_79

mRNA and Protein(s)

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
NM_001330595.1 → 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, BC037491, BX648833, DC372305

Consensus CDS

CCDS81779.1

UniProtKB/Swiss-Prot

P49917

UniProtKB/TrEMBL

A0A0C4DGV9, A8K8Q4

Related

ENSP00000480814.1, ENST00000614526.1
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
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
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
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
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
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
NM_001352604.1 → 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
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

Related

ENSP00000349393.3, ENST00000356922.5

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
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