LIG4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000012 single strand break repair	IDA PMID:8798671 DNA ligase IV from HeLa cell nuclei.	MARK AS OVER ANNOTATED	Summary: Purified LIG4 from HeLa nuclei joins single-strand breaks (nicks) in a double-stranded polymer in vitro. Reason: The assay shows nick-ligation activity, not participation in cellular single-strand break repair. In cells, SSBR ligation is performed by LIG3/XRCC1 and LIG1; LIG4 acts at double-strand breaks in NHEJ. The activity is captured by DNA ligase (ATP) activity. Supporting Evidence: PMID:8798671 The purified protein effectively joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0000287 magnesium ion binding	IDA PMID:29980672 Structures of DNA-bound human ligase IV catalytic core revea...	KEEP AS NON CORE	Summary: Metal-specificity screen with the purified LIG4 catalytic core; Mg2+ is the physiological cofactor (Mn2+, Ca2+, Ni2+, Co2+ also support ligation). Reason: Correct cofactor binding needed for nick sealing, but a cofactor property rather than the defining function. Supporting Evidence: PMID:29980672 The absence of metal ions in these structures was surprising; therefore, the magnesium-dependence of LigIV activity was assayed on both unadenylated and pre-adenylated nicked substrates. file:human/LIG4/LIG4-uniprot.txt Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
GO:0000781 chromosome, telomeric region	IC PMID:23275564 Human LIGIV is synthetically lethal with the loss of Rad54B-...	KEEP AS NON CORE	Summary: Curator inference that LIG4 is at telomeres, from its requirement for NHEJ-mediated chromosome fusions after telomere dysfunction (TRF2 dominant negative). Reason: LIG4 ligates deprotected telomeres in classical NHEJ (telomere fusions after TRF2 loss), so it must act at telomeric ends in that context; this is a conditional, damage-induced location rather than a constitutive one. Supporting Evidence: PMID:23275564 LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction
GO:0000793 condensed chromosome	IDA PMID:12589063 In vitro and in vivo interactions of DNA ligase IV with a su...	KEEP AS NON CORE	Summary: LIG4 colocalizes with the condensin subunit hCAP-E (SMC4) on mitotic chromosomes (abstract-only cache). Reason: Direct immunofluorescence observation by the curator; the functional meaning of LIG4 on mitotic chromosomes is not established, so non-core. Supporting Evidence: PMID:12589063 mitotic cells display colocalization of both polypeptides on mitotic chromosomes
GO:0001701 in utero embryonic development	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4, whose knockout causes late embryonic lethality. Reason: Embryonic lethality reflects unrepaired DSBs (neuronal apoptosis) rather than a dedicated developmental function. This is a necessity phenotype of a housekeeping DNA repair ligase, not evidence that LIG4 does work specific to embryonic development, so it is marked over-annotated, as for NBN GO:0001701 and for the other knockout-phenotype rows here (neuron apoptosis, stem cell maintenance). The term is not removed because the loss-of-function lethality is real. Human LIG4-null somatic cells are viable, and human LIG4 syndrome is hypomorphic. Supporting Evidence: PMID:9823897 Here we show that inactivation of the ligase IV gene in mice leads to late embryonic lethality. PMID:9889105 targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system
GO:0002328 pro-B cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from mouse Lig4; lymphopoiesis is blocked in Lig4-null mice because V(D)J joining fails. Reason: Pro-B cell differentiation fails secondary to the V(D)J recombination defect; LIG4 is not a differentiation regulator. Non-core. Supporting Evidence: PMID:9823897 Lymphopoiesis in these mice is blocked and V(D)J joining does not occur.
GO:0003677 DNA binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: PAINT IBA for DNA binding, from the LIG4 clade. Reason: LIG4 binds DNA through its DNA-binding domain and encircles nicked DNA during catalysis; correct, but DNA binding is part of the ligase mechanism rather than a separate function. Supporting Evidence: PMID:29980672 Results from structural and mutagenesis experiments unveil a dynamic LigIV DNA encirclement mechanism
GO:0003677 DNA binding	IDA PMID:29980672 Structures of DNA-bound human ligase IV catalytic core revea...	KEEP AS NON CORE	Summary: Crystal structures of the LIG4 catalytic core bound to nicked DNA. Reason: Direct structural evidence of DNA binding; DNA binding is intrinsic to the ligase activity, so non-core. Supporting Evidence: PMID:29980672 Results from structural and mutagenesis experiments unveil a dynamic LigIV DNA encirclement mechanism
GO:0003677 DNA binding	IDA PMID:8798671 DNA ligase IV from HeLa cell nuclei.	KEEP AS NON CORE	Summary: Purified LIG4 binds and ligates nicked DNA substrates. Reason: DNA binding is intrinsic to the ligase activity, so non-core. Supporting Evidence: PMID:8798671 The purified protein effectively joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction.
GO:0003677 DNA binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro-based DNA binding. Reason: Consistent with structural evidence; DNA binding is intrinsic to ligase activity, so non-core. Supporting Evidence: PMID:29980672 Results from structural and mutagenesis experiments unveil a dynamic LigIV DNA encirclement mechanism
GO:0003909 DNA ligase activity	IDA PMID:12517771 Requirement for XRCC4 and DNA ligase IV in alignment-based g...	MODIFY	Summary: XRCC4/LIG4 supplementation of XR-1 extracts restores gap filling and ligation of a DSB. Reason: LIG4 ligase activity is ATP dependent; use the specific child GO:0003910, which the gene carries by IDA, IMP and IBA. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: PMID:12517771 In the nonhomologous end joining pathway of DNA double-strand break repair, the ligation step is catalyzed by a complex of XRCC4 and DNA ligase IV.
GO:0003909 DNA ligase activity	IDA PMID:17290226 XRCC4:DNA ligase IV can ligate incompatible DNA ends and can...	MODIFY	Summary: XRCC4:LIG4 ligates incompatible DNA ends and across 1-nt gaps. Reason: Use the specific ATP-dependent child term GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: PMID:17290226 human XRCC4:DNA ligase IV can ligate two double-strand DNA ends that have fully incompatible short 3' overhang configurations with no potential for base pairing
GO:0003909 DNA ligase activity	IDA PMID:19589734 Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta,...	MODIFY	Summary: Kinetics of purified LIG4/XRCC4 on nicked and linear duplex substrates; LIG4/XRCC4 catalyses a single ligation event per molecule. Reason: Use the specific ATP-dependent child term GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: PMID:19589734 hLigIIIbeta and the hLigIIIalpha/XRCC1 and hLigIV/XRCC4 complexes are active on both nicked and linear duplex DNA substrates
GO:0003909 DNA ligase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro-based DNA ligase activity. Reason: Use the specific ATP-dependent child term GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: file:human/LIG4/LIG4-uniprot.txt Reaction=ATP + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho-(deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + diphosphate.; EC=6.5.1.1
GO:0003909 DNA ligase activity	TAS Reactome:R-GGA-353298	MODIFY	Summary: Reactome (chicken NHEJ reaction, propagated) DNA ligase activity for the XRCC4:LIG4 step of NHEJ. Reason: Use the specific ATP-dependent child term GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0003909 DNA ligase activity	TAS Reactome:R-HSA-175258	MODIFY	Summary: Reactome HIV 2-LTR circle formation, in which Ku, XRCC4 and LIG4 join the ends of unintegrated viral DNA. Reason: The ligation of viral DNA ends is the same ATP-dependent NHEJ ligase activity; use GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: Reactome:R-HSA-175258 This reaction requires Ku, XRCC4 and ligase 4.
GO:0003909 DNA ligase activity	TAS Reactome:R-HSA-5693604	MODIFY	Summary: Reactome XRCC4:LIG4 ligation of DSB ends in NHEJ. Reason: Use the specific ATP-dependent child term GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: Reactome:R-HSA-5693604 catalyzes ligation of DNA double strand break (DSB) ends during non-homologous end joining (NHEJ)
GO:0003910 DNA ligase (ATP) activity	EXP PMID:9809069 DNA ligase IV is essential for V(D)J recombination and DNA d...	ACCEPT	Summary: LIG4 complementation of LIG4-null human pre-B cells; LIG4 is the NHEJ ligase. Reason: Core catalytic activity of LIG4. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination. file:human/LIG4/LIG4-uniprot.txt Reaction=ATP + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho-(deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + diphosphate.; EC=6.5.1.1
GO:0003910 DNA ligase (ATP) activity	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBA for DNA ligase (ATP) activity across LIG4 orthologs (yeast Dnl4, Arabidopsis LIG4, mouse, rat, human). Reason: Ancestral, experimentally confirmed activity of the LIG4 clade. Supporting Evidence: PMID:29980672 DNA ligase IV (LigIV) performs the final DNA nick-sealing step of classical nonhomologous end-joining
GO:0003910 DNA ligase (ATP) activity	IDA PMID:22192310 A high-throughput scintillation proximity-based assay for hu...	ACCEPT	Summary: Scintillation-proximity screen for inhibitors of adenylate transfer from Lig4-AMP to DNA. Reason: Direct assay of the second step of the ATP-dependent ligase reaction. Supporting Evidence: PMID:22192310 Rabeprazole and U73122 were found to specifically block the adenylate transfer step and DNA rejoining
GO:0003910 DNA ligase (ATP) activity	IDA PMID:23523427 Structure of the catalytic region of DNA ligase IV in comple...	ACCEPT	Summary: Crystal structure of the LIG4 catalytic region (1-609) with an Artemis peptide; UniProt cites this paper for the EC 6.5.1.1 reaction. Reason: Defers to the curator (full text not cached); the activity is well established. Supporting Evidence: file:human/LIG4/LIG4-uniprot.txt Reaction=ATP + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho-(deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + diphosphate.; EC=6.5.1.1 PMID:29980672 DNA ligase IV (LigIV) performs the final DNA nick-sealing step of classical nonhomologous end-joining
GO:0003910 DNA ligase (ATP) activity	IDA PMID:29980672 Structures of DNA-bound human ligase IV catalytic core revea...	ACCEPT	Summary: Crystal structures of LIG4 catalytic core in lysyl-AMP and DNA-adenylate states, with mutagenesis of nick sealing. Reason: Direct biochemical and structural evidence of ATP-dependent nick sealing. Supporting Evidence: PMID:29980672 DNA ligase IV (LigIV) performs the final DNA nick-sealing step of classical nonhomologous end-joining
GO:0003910 DNA ligase (ATP) activity	IDA PMID:8798671 DNA ligase IV from HeLa cell nuclei.	ACCEPT	Summary: Purified LIG4 joins nicks in an ATP-dependent reaction and forms an enzyme-adenylate complex. Reason: Direct biochemical evidence. Supporting Evidence: PMID:8798671 The purified protein effectively joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction.
GO:0003910 DNA ligase (ATP) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic ATP-dependent ligase activity (EC 6.5.1.1, InterPro, mouse ortholog). Reason: Matches experimental evidence. Supporting Evidence: file:human/LIG4/LIG4-uniprot.txt Reaction=ATP + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho-(deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + diphosphate.; EC=6.5.1.1
GO:0003910 DNA ligase (ATP) activity	IMP PMID:29980672 Structures of DNA-bound human ligase IV catalytic core revea...	ACCEPT	Summary: Mutagenesis of the LIG4 catalytic core (active site, interdomain contacts) impairs nick sealing. Reason: Mutational evidence that the catalytic core residues are required for activity. Supporting Evidence: PMID:29980672 extensive interdomain interactions and active site phosphoanhydride coordination, all of which are required for efficient DNA nick sealing
GO:0005515 protein binding	IPI PMID:11702069 Crystal structure of an Xrcc4-DNA ligase IV complex.	REMOVE	Summary: Physical interaction with XRCC4 (PMID:11702069). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:12589063 In vitro and in vivo interactions of DNA ligase IV with a su...	REMOVE	Summary: Physical interaction with SMC4 (hCAP-E, condensin) (PMID:12589063). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-SMC4 association is captured by no accepted functional term (role unknown).
GO:0005515 protein binding	IPI PMID:16439205 XLF interacts with the XRCC4-DNA ligase IV complex to promot...	REMOVE	Summary: Physical interaction with NHEJ1 (XLF) (PMID:16439205). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-NHEJ1 association is captured by the nonhomologous end joining complex (GO:0070419) term.
GO:0005515 protein binding	IPI PMID:17290226 XRCC4:DNA ligase IV can ligate incompatible DNA ends and can...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:17290226). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:17389648 Conserved interactions of the splicing factor Ntr1/Spp382 wi...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:17389648). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:17396150 A novel human AP endonuclease with conserved zinc-finger-lik...	REMOVE	Summary: Physical interaction with APLF (PMID:17396150). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-APLF association is captured by the NHEJ process terms.
GO:0005515 protein binding	IPI PMID:19589734 Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta,...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:19589734). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:21070942 XLF regulates filament architecture of the XRCC4·ligase IV c...	REMOVE	Summary: Physical interaction with XRCC4 (isoform 2) (PMID:21070942). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:22529269 Artemis C-terminal region facilitates V(D)J recombination th...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:22529269). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:22529269 Artemis C-terminal region facilitates V(D)J recombination th...	REMOVE	Summary: Physical interaction with DCLRE1C (Artemis) (PMID:22529269). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-DCLRE1C association is captured by the NHEJ process and complex terms.
GO:0005515 protein binding	IPI PMID:22658747 Structural insights into the role of domain flexibility in h...	REMOVE	Summary: Physical interaction with XRCC4 (isoform 2) (PMID:22658747). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:23178593 APLF promotes the assembly and activity of non-homologous en...	REMOVE	Summary: Physical interaction with APLF (PMID:23178593). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-APLF association is captured by the NHEJ process terms.
GO:0005515 protein binding	IPI PMID:23219551 Structural basis of DNA ligase IV-Artemis interaction in non...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:23219551). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:23219551 Structural basis of DNA ligase IV-Artemis interaction in non...	REMOVE	Summary: Physical interaction with DCLRE1C (Artemis) (PMID:23219551). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-DCLRE1C association is captured by the NHEJ process and complex terms.
GO:0005515 protein binding	IPI PMID:23523427 Structure of the catalytic region of DNA ligase IV in comple...	REMOVE	Summary: Physical interaction with DCLRE1C (Artemis) (PMID:23523427). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-DCLRE1C association is captured by the NHEJ process and complex terms.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	REMOVE	Summary: Physical interaction with XRCC4 (PMID:25416956). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:25910212). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:25934149 Lysine 271 but not lysine 210 of XRCC4 is required for the n...	REMOVE	Summary: Physical interaction with LIG4 itself (PMID:25934149). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-LIG4 association is captured by no functional term.
GO:0005515 protein binding	IPI PMID:25934149 Lysine 271 but not lysine 210 of XRCC4 is required for the n...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:25934149). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:28514442). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	REMOVE	Summary: Physical interaction with APLF (PMID:28514442). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-APLF association is captured by the NHEJ process terms.
GO:0005515 protein binding	IPI PMID:31548606 The nucleoskeleton protein IFFO1 immobilizes broken DNA and ...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:31548606). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:31548606 The nucleoskeleton protein IFFO1 immobilizes broken DNA and ...	REMOVE	Summary: Physical interaction with NHEJ1 (XLF) (PMID:31548606). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-NHEJ1 association is captured by the nonhomologous end joining complex (GO:0070419) term.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Physical interaction with XRCC4 (PMID:32296183). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:33961781). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: Physical interaction with APLF (PMID:33961781). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-APLF association is captured by the NHEJ process terms.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:40205054). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	REMOVE	Summary: Physical interaction with APLF (PMID:40205054). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-APLF association is captured by the NHEJ process terms.
GO:0005515 protein binding	IPI PMID:9242410 Activity of DNA ligase IV stimulated by complex formation wi...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:9242410). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:9259561 Mammalian DNA double-strand break repair protein XRCC4 inter...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:9259561). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005515 protein binding	IPI PMID:9809069 DNA ligase IV is essential for V(D)J recombination and DNA d...	REMOVE	Summary: Physical interaction with XRCC4 (PMID:9809069). Reason: Bare protein binding is uninformative under the protein-binding policy; removal does not dispute the interaction. The functional context of the LIG4-XRCC4 association is captured by the DNA ligase IV complex (GO:0032807) term accepted in this review.
GO:0005524 ATP binding	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBA for ATP binding in the LIG4 clade. Reason: LIG4 is an ATP-dependent ligase that forms a lysyl-AMP intermediate; ATP binding is required for catalysis. Supporting Evidence: PMID:29980672 the crystal structure of the catalytic core of human LigIV in complex with a nicked nucleic acid substrate in two distinct states-an open lysyl-AMP intermediate, and a closed DNA-adenylate form
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic ATP binding (InterPro ATP-dependent DNA ligase domains, mouse ortholog). Reason: Consistent with the ATP-dependent mechanism. Supporting Evidence: file:human/LIG4/LIG4-uniprot.txt Reaction=ATP + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho-(deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + diphosphate.; EC=6.5.1.1
GO:0005634 nucleus	EXP PMID:21982441 XRCC4 controls nuclear import and distribution of Ligase IV ...	ACCEPT	Summary: LIG4 nuclear import depends on complex formation with XRCC4 (fluorescent fusion proteins in HT-1080 cells). Reason: LIG4 acts on chromosomal DSBs in the nucleus; experimental localization. Supporting Evidence: PMID:21982441 When Ligase IV was co-expressed with XRCC4, both proteins formed the natural complex, and Ligase IV was not only efficiently imported but also resembled the sub-nuclear distribution of XRCC4.
GO:0005634 nucleus	EXP PMID:24984242 DNA Ligase IV regulates XRCC4 nuclear localization.	ACCEPT	Summary: LIG4 C-terminal region (NLS, BRCT I, XIR) is needed for nuclear localization of XRCC4 and XLF. Reason: Experimental nuclear localization; consistent with function. Supporting Evidence: PMID:24984242 a C-terminal region of Ligase IV (aa 620-800), which encompasses a NLS, the BRCT I, and the XRCC4 interacting region (XIR), is essential for nuclear localization of its co-factor XRCC4
GO:0005634 nucleus	IDA PMID:12589063 In vitro and in vivo interactions of DNA ligase IV with a su...	ACCEPT	Summary: Immunofluorescence shows LIG4 in the interphase nucleus colocalizing with hCAP-E. Reason: Experimental nuclear localization. Supporting Evidence: PMID:12589063 Immunofluorescence studies reveal colocalization of DNA ligase IV and hCAP-E in the interphase nucleus
GO:0005634 nucleus	IDA PMID:25934149 Lysine 271 but not lysine 210 of XRCC4 is required for the n...	ACCEPT	Summary: XRCC4 K271 is needed for nuclear localization of XRCC4 and LIG4 and for DSB repair. Reason: Experimental nuclear localization tied to DSB repair function. Supporting Evidence: PMID:25934149 Lys271, but not Lys210, of XRCC4 is required for the nuclear localization of XRCC4 and LIG4
GO:0005634 nucleus	IDA PMID:8798671 DNA ligase IV from HeLa cell nuclei.	ACCEPT	Summary: LIG4 purified from HeLa cell nuclei. Reason: Biochemical purification from nuclei; consistent localization. Supporting Evidence: PMID:8798671 Antibodies have been raised against predicted peptide sequences of DNA ligase IV and used to identify the enzyme during purification from HeLa cell nuclei.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular location mapping to nucleus. Reason: Rests on curated experimental nuclear localization. Supporting Evidence: PMID:21982441 When Ligase IV was co-expressed with XRCC4, both proteins formed the natural complex, and Ligase IV was not only efficiently imported but also resembled the sub-nuclear distribution of XRCC4.
GO:0005634 nucleus	NAS PMID:19332554 Structural and functional interaction between the human DNA ...	ACCEPT	Summary: Nucleus (NAS) from the XRCC4-LIG4 BRCT structure paper. Reason: Consistent with experimental localization. Supporting Evidence: PMID:21982441 When Ligase IV was co-expressed with XRCC4, both proteins formed the natural complex, and Ligase IV was not only efficiently imported but also resembled the sub-nuclear distribution of XRCC4.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nucleoplasm from HPA immunofluorescence. Reason: LIG4 acts on chromosomal DSBs in the nucleoplasm; consistent with its function. Supporting Evidence: PMID:21982441 When Ligase IV was co-expressed with XRCC4, both proteins formed the natural complex, and Ligase IV was not only efficiently imported but also resembled the sub-nuclear distribution of XRCC4.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-175177	ACCEPT	Summary: Reactome nucleoplasm location, recruitment of XRCC4:LIG4 to HIV viral DNA. Reason: Nuclear location of the LIG4 complex; consistent with experimental localization. Supporting Evidence: Reactome:R-HSA-175177 XRCC4 and DNA ligase 4 are recruited to the complex containing viral DNA.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-175258	ACCEPT	Summary: Reactome nucleoplasm location, HIV 2-LTR circle formation. Reason: Nuclear location of the LIG4 complex; consistent with experimental localization. Supporting Evidence: Reactome:R-HSA-175258 This reaction requires Ku, XRCC4 and ligase 4.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5687360	ACCEPT	Summary: Reactome nucleoplasm location, POLM/POLL gap filling in the NHEJ synaptic complex containing XRCC4:LIG4. Reason: Nucleoplasmic NHEJ context. Supporting Evidence: Reactome:R-HSA-5687360 present at DNA DSB ends positioned for ligation in the synaptic complex containing XRCC5:XRCC6 (Ku), PRKDC (DNA-PKcs), DCLRE1C (ARTEMIS), XRCC4:LIG4 and NHEJ1 (XLF)
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693574	ACCEPT	Summary: Reactome nucleoplasm location, recruitment of XRCC4:LIG4 to the synaptic complex. Reason: Nucleoplasmic NHEJ context. Supporting Evidence: Reactome:R-HSA-5693574 is recruited to the synaptic complex consisting of PRKDC (DNA-PKcs), XRCC5, XRCC6, DCLRE1C (ARTEMIS) and ligatable DNA double strand break (DSB) ends
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693604	ACCEPT	Summary: Reactome nucleoplasm location, XRCC4:LIG4 ligation of DSB ends. Reason: Nucleoplasmic NHEJ context. Supporting Evidence: Reactome:R-HSA-5693604 catalyzes ligation of DNA double strand break (DSB) ends during non-homologous end joining (NHEJ)
GO:0005958 DNA-dependent protein kinase-DNA ligase 4 complex	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBA for the DNA-dependent protein kinase-DNA ligase 4 complex (vertebrate LIG4 node). Reason: LIG4/XRCC4 assembles with Ku and DNA-PKcs (and XLF) into NHEJ synaptic supercomplexes on DNA ends. Supporting Evidence: PMID:34352203 we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA
GO:0005958 DNA-dependent protein kinase-DNA ligase 4 complex	IDA PMID:15194694 Phosphorylation and regulation of DNA ligase IV stability by...	ACCEPT	Summary: Full-length LIG4 in complex with XRCC4 is an in vitro DNA-PK substrate (abstract-only cache). Reason: Defers to the curator; association of LIG4/XRCC4 with DNA-PK is supported by structural work. Supporting Evidence: PMID:15194694 Also the full-length Lig4 protein, in complex with XRCC4, was an in vitro substrate for DNA-PK. PMID:34352203 we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA
GO:0005958 DNA-dependent protein kinase-DNA ligase 4 complex	IDA PMID:34352203 Cryo-EM of NHEJ supercomplexes provides insights into DNA re...	ACCEPT	Summary: Cryo-EM structures of NHEJ supercomplexes containing Ku70/80, DNA-PKcs, XRCC4, XLF and LIG4 on DNA. Reason: Direct structural evidence. Supporting Evidence: PMID:34352203 we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA
GO:0005958 DNA-dependent protein kinase-DNA ligase 4 complex	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (ARBA/ortholog) DNA-PK-LIG4 complex. Reason: Consistent with structural evidence. Supporting Evidence: PMID:34352203 we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA
GO:0005958 DNA-dependent protein kinase-DNA ligase 4 complex	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse Lig4 for the DNA-PK-LIG4 complex. Reason: Consistent with structural evidence on the human proteins. Supporting Evidence: PMID:34352203 we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA
GO:0006281 DNA repair	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based DNA repair. Reason: Broad but correct; LIG4 is the ligase of NHEJ DSB repair. More specific terms are annotated. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0006284 base-excision repair	IDA PMID:19589734 Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta,...	MARK AS OVER ANNOTATED	Summary: Base-excision repair, from kinetics of purified LIG4/XRCC4 on nicked substrates. Reason: The paper measures nick ligation in vitro and itself frames LIG4 as the NHEJ ligase while LIG1/LIG3 complete nick-ligation pathways. There is no evidence that LIG4 participates in cellular BER. Supporting Evidence: PMID:19589734 Since hLigI and hLigIII are primarily involved in pathways that are completed by nick ligation whereas hLigIV is a key factor in the major pathway that repairs DNA double strand breaks
GO:0006297 nucleotide-excision repair, DNA gap filling	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetic inference seeded by the experimental gap-filling rows, which concern non-homologous end joining rather than nucleotide-excision repair; redirected with them. Reason: The term on this phylogenetic row is seeded by the two experimental rows of this review, which describe gap filling and ligation during non-homologous end joining of double-strand breaks and are redirected to double-strand break repair via nonhomologous end joining. The inherited function is therefore real but mis-termed at its seeds, and no LIG4 ortholog has a role in nucleotide-excision repair. The phylogenetic row carries the same claim as the experimental rows and is redirected in the same way, to a term that LIG4 also carries from independent evidence, rather than removed. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: PANTHER:PTN000048698 SOURCE BAD LIG4 clade node carrying the NER gap-filling IBD; the only descendant evidence is human LIG4. UniProtKB:P49917 · LIG4 SOURCE BAD Human LIG4 IDA rows (PMID:12517771, PMID:17290226) describe gap filling at NHEJ double-strand break ends, mis-termed as NER gap filling. Proposed replacements: double-strand break repair via nonhomologous end joining Supporting Evidence: PMID:12517771 The results imply that XRCC4 and ligase IV are essential for alignment-based gap filling, as well as for final ligation of the breaks.
GO:0006297 nucleotide-excision repair, DNA gap filling	IDA PMID:12517771 Requirement for XRCC4 and DNA ligase IV in alignment-based g...	MODIFY	Summary: XRCC4/LIG4 restores alignment-based gap filling and accurate end joining of a site-specific DSB in XR-1 cell extracts. Reason: The experiment concerns gap filling and ligation within NHEJ of a double-strand break; GO:0006297 is the NER gap-filling term and is the wrong process. The correct process is double-strand break repair via nonhomologous end joining. Proposed replacements: double-strand break repair via nonhomologous end joining Supporting Evidence: PMID:12517771 The results imply that XRCC4 and ligase IV are essential for alignment-based gap filling, as well as for final ligation of the breaks.
GO:0006297 nucleotide-excision repair, DNA gap filling	IDA PMID:17290226 XRCC4:DNA ligase IV can ligate incompatible DNA ends and can...	MODIFY	Summary: XRCC4:LIG4 ligates across 1-nt gaps at DNA ends with short terminal annealing. Reason: The experiment concerns ligation across gaps during NHEJ of double-strand ends; GO:0006297 is the NER gap-filling term and is the wrong process. Proposed replacements: double-strand break repair via nonhomologous end joining Supporting Evidence: PMID:17290226 at DNA ends that share 1-4 annealed base pairs, XRCC4:DNA ligase IV can ligate across gaps of 1 nt
GO:0006302 double-strand break repair	IDA PMID:19589734 Distinct kinetics of human DNA ligases I, IIIalpha, IIIbeta,...	ACCEPT	Summary: DSB repair, from kinetics of purified LIG4/XRCC4 on linear duplex substrates. Reason: LIG4 ligates DSB ends in NHEJ; correct. Supporting Evidence: PMID:19589734 hLigIV/XRCC4, which is a key component of the major non-homologous end joining (NHEJ) pathway
GO:0006302 double-strand break repair	IDA PMID:9242410 Activity of DNA ligase IV stimulated by complex formation wi...	ACCEPT	Summary: XRCC4 stimulates LIG4 ligation of double-strand breaks in a cell-free system. Reason: Direct evidence of DSB joining. Supporting Evidence: PMID:9242410 Ligation of DNA double-strand breaks in a cell-free system by DNA ligase IV is increased fivefold by purified XRCC4
GO:0006302 double-strand break repair	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse Lig4 for double-strand break repair. Reason: Consistent with human evidence. Supporting Evidence: PMID:9809069 the targeted disruption of both DNA ligase IV alleles in a human pre-B cell line renders the cells sensitive to ionizing radiation and ablates V(D)J recombination
GO:0006303 double-strand break repair via nonhomologous end joining	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBA for NHEJ across LIG4 orthologs (yeast, fission yeast, fly, plant, mouse, human). Reason: Ancestral and experimentally confirmed core process. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0006303 double-strand break repair via nonhomologous end joining	IDA PMID:12517771 Requirement for XRCC4 and DNA ligase IV in alignment-based g...	ACCEPT	Summary: XRCC4/LIG4 restores accurate end joining of a DSB in XR-1 extracts. Reason: Direct evidence for NHEJ. Supporting Evidence: PMID:12517771 In the nonhomologous end joining pathway of DNA double-strand break repair, the ligation step is catalyzed by a complex of XRCC4 and DNA ligase IV.
GO:0006303 double-strand break repair via nonhomologous end joining	IDA PMID:17290226 XRCC4:DNA ligase IV can ligate incompatible DNA ends and can...	ACCEPT	Summary: XRCC4:LIG4 flexibly ligates incompatible ends in NHEJ. Reason: Direct evidence for NHEJ ligation. Supporting Evidence: PMID:17290226 XRCC4 and DNA ligase IV form a complex that is essential for the repair of all double-strand DNA breaks by the nonhomologous DNA end joining pathway in eukaryotes.
GO:0006303 double-strand break repair via nonhomologous end joining	IDA PMID:19332554 Structural and functional interaction between the human DNA ...	ACCEPT	Summary: Structure of XRCC4 bound to the LIG4 tandem BRCT; disruption radiosensitizes cells. Reason: Defines the NHEJ ligation complex architecture and its requirement for DSB repair. Supporting Evidence: PMID:19332554 It relies on the XRCC4/DNA ligase IV complex to reseal DNA strands.
GO:0006303 double-strand break repair via nonhomologous end joining	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic NHEJ. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0006303 double-strand break repair via nonhomologous end joining	IGI PMID:23275564 Human LIGIV is synthetically lethal with the loss of Rad54B-...	ACCEPT	Summary: Genetic interaction with TERF2; LIG4 required for chromosome fusions after TRF2 dominant-negative expression. Reason: Telomere fusions after TRF2 loss are classical NHEJ events ligated by LIG4, as the genetic interaction in PMID:23275564 shows. Supporting Evidence: PMID:23275564 LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction
GO:0006303 double-strand break repair via nonhomologous end joining	IMP PMID:9809069 DNA ligase IV is essential for V(D)J recombination and DNA d...	ACCEPT	Summary: LIG4-null human pre-B cells are radiosensitive; only LIG4 restores repair. Reason: Direct genetic evidence that LIG4 is the NHEJ ligase. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0006303 double-strand break repair via nonhomologous end joining	TAS Reactome:R-GGA-353423	ACCEPT	Summary: Reactome (chicken reaction) NHEJ. Reason: Consistent with human experimental evidence. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0006303 double-strand break repair via nonhomologous end joining	TAS Reactome:R-HSA-5693571	ACCEPT	Summary: Reactome NHEJ pathway. Reason: Consistent with experimental evidence. Supporting Evidence: Reactome:R-HSA-5693604 catalyzes ligation of DNA double strand break (DSB) ends during non-homologous end joining (NHEJ)
GO:0006310 DNA recombination	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: InterPro-based DNA recombination. Reason: LIG4 completes V(D)J recombination and class switch recombination by joining their DSBs; DNA recombination is true but broad, and the specific V(D)J terms are accepted. Supporting Evidence: PMID:20192759 NHEJ is critical not only for the repair of pathologic DSBs as in chromosomal translocations, but also for the repair of physiologic DSBs created during variable (diversity) joining [V(D)J] recombination and class switch recombination (CSR).
GO:0007417 central nervous system development	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4; knockout causes massive apoptosis in the developing CNS. Reason: Neural phenotypes are secondary to unrepaired DSBs in proliferating neural progenitors, a necessity phenotype of a housekeeping DNA repair ligase rather than work LIG4 does in CNS development, so the term is marked over-annotated (same rule as GO:0001701). Human LIG4 syndrome includes microcephaly. Supporting Evidence: PMID:9889105 targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system
GO:0008283 cell population proliferation	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4; Lig4-null fibroblasts show growth defects and premature senescence. Reason: Reduced proliferation is an indirect consequence of unrepaired DNA damage, not a process LIG4 executes. Supporting Evidence: PMID:9823897 Ligase IV-deficient embryonic fibroblasts also show marked sensitivity to ionizing radiation, growth defects and premature senescence.
GO:0010165 response to X-ray	IMP PMID:9809069 DNA ligase IV is essential for V(D)J recombination and DNA d...	KEEP AS NON CORE	Summary: LIG4-null human pre-B cells are sensitive to ionizing radiation (X-rays). Reason: LIG4 repairs IR-induced DSBs; response-to-radiation terms are true but describe the cellular outcome of its NHEJ function. Supporting Evidence: PMID:9809069 the targeted disruption of both DNA ligase IV alleles in a human pre-B cell line renders the cells sensitive to ionizing radiation and ablates V(D)J recombination
GO:0010212 response to ionizing radiation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA electronic response to ionizing radiation. Reason: As for the other radiation-response rows, true but non-core. Supporting Evidence: PMID:9809069 the targeted disruption of both DNA ligase IV alleles in a human pre-B cell line renders the cells sensitive to ionizing radiation and ablates V(D)J recombination
GO:0010332 response to gamma radiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from mouse Lig4 for response to gamma radiation. Reason: As for the other radiation-response rows, true but non-core. Supporting Evidence: PMID:9823897 Ligase IV-deficient embryonic fibroblasts also show marked sensitivity to ionizing radiation, growth defects and premature senescence.
GO:0016874 ligase activity	IDA PMID:9242410 Activity of DNA ligase IV stimulated by complex formation wi...	MODIFY	Summary: XRCC4-stimulated ligation of DNA double-strand breaks by LIG4. Reason: Ligase activity is correct but very general; LIG4 is an ATP-dependent DNA ligase, so use GO:0003910. Proposed replacements: DNA ligase (ATP) activity Supporting Evidence: PMID:9242410 Ligation of DNA double-strand breaks in a cell-free system by DNA ligase IV is increased fivefold by purified XRCC4
GO:0032807 DNA ligase IV complex	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBA for the DNA ligase IV complex (LIG4 with XRCC4 or yeast Lif1). Reason: The LIG4-XRCC4 complex is conserved and is the NHEJ ligation unit. Supporting Evidence: PMID:19332554 It relies on the XRCC4/DNA ligase IV complex to reseal DNA strands.
GO:0032807 DNA ligase IV complex	IMP PMID:9809069 DNA ligase IV is essential for V(D)J recombination and DNA d...	ACCEPT	Summary: LIG4 complex with XRCC4 in human pre-B cells. Reason: Consistent with structural and biochemical evidence for the LIG4-XRCC4 complex. Supporting Evidence: PMID:9242410 Ligation of DNA double-strand breaks in a cell-free system by DNA ligase IV is increased fivefold by purified XRCC4
GO:0032807 DNA ligase IV complex	IPI PMID:19332554 Structural and functional interaction between the human DNA ...	ACCEPT	Summary: Crystal structure of XRCC4 with the LIG4 BRCT tandem. Reason: Direct structural evidence for the DNA ligase IV complex. Supporting Evidence: PMID:19332554 Here we report the high-resolution crystal structure of human XRCC4 bound to the carboxy-terminal tandem BRCT repeat of DNA ligase IV.
GO:0033077 T cell differentiation in thymus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from mouse Lig4 for T cell differentiation in thymus. Reason: Thymocyte development fails secondary to defective TCR V(D)J recombination; developmental, non-core. Supporting Evidence: PMID:9823897 Lymphopoiesis in these mice is blocked and V(D)J joining does not occur.
GO:0033151 V(D)J recombination	IDA PMID:9809069 DNA ligase IV is essential for V(D)J recombination and DNA d...	ACCEPT	Summary: LIG4-null human pre-B cells cannot perform V(D)J recombination; rescued only by LIG4. Reason: Direct genetic evidence; LIG4 ligates the coding and signal joints. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0033151 V(D)J recombination	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic V(D)J recombination. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0033152 immunoglobulin V(D)J recombination	IBA GO_REF:0000033	ACCEPT	Summary: PAINT IBA for immunoglobulin V(D)J recombination (vertebrate LIG4 node). Reason: LIG4 is required for V(D)J joining in pre-B cells. Supporting Evidence: PMID:9809069 the targeted disruption of both DNA ligase IV alleles in a human pre-B cell line renders the cells sensitive to ionizing radiation and ablates V(D)J recombination
GO:0033153 T cell receptor V(D)J recombination	ISS GO_REF:0000024	ACCEPT	Summary: ISS from mouse Lig4 for T cell receptor V(D)J recombination. Reason: LIG4 ligates the DSBs of V(D)J recombination at both Ig and TCR loci. Supporting Evidence: PMID:9823897 Lymphopoiesis in these mice is blocked and V(D)J joining does not occur.
GO:0035019 somatic stem cell population maintenance	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4; hypomorphic Lig4(Y288C) mice show progressive loss of haematopoietic stem cells with age. Reason: Stem-cell decline reflects accumulated unrepaired DSBs (an indirect consequence of reduced NHEJ), not a process LIG4 performs. Supporting Evidence: PMID:17554302 Diminished DNA double-strand break repair in the Lig4(Y288C) strain causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during ageing
GO:0043524 negative regulation of neuron apoptotic process	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4 for negative regulation of neuron apoptotic process. Reason: Neuronal apoptosis in Lig4 deficiency is triggered by unrepaired DSBs (p53-dependent); LIG4 prevents it indirectly by repairing DNA, not by regulating apoptosis. Supporting Evidence: PMID:9889105 targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system
GO:0045190 isotype switching	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS from mouse Lig4 for isotype switching. Reason: Class switch recombination is completed by NHEJ joining of switch-region DSBs, in which LIG4 contributes the ligation (with alternative end joining as backup). True but a specialised context of its NHEJ function. Supporting Evidence: PMID:20192759 NHEJ is critical not only for the repair of pathologic DSBs as in chromosomal translocations, but also for the repair of physiologic DSBs created during variable (diversity) joining [V(D)J] recombination and class switch recombination (CSR).
GO:0048146 positive regulation of fibroblast proliferation	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4 for positive regulation of fibroblast proliferation. Reason: Growth defects of Lig4-null fibroblasts reflect unrepaired DNA damage; LIG4 does not regulate proliferation. Supporting Evidence: PMID:9823897 Ligase IV-deficient embryonic fibroblasts also show marked sensitivity to ionizing radiation, growth defects and premature senescence.
GO:0050769 positive regulation of neurogenesis	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4 for positive regulation of neurogenesis. Reason: Neural defects are an indirect consequence of DSB-induced apoptosis of neural progenitors; LIG4 does not regulate neurogenesis. Supporting Evidence: PMID:9889105 targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system
GO:0051276 chromosome organization	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4 for chromosome organization. Reason: Chromosomal breaks and rearrangements in Lig4 deficiency reflect failed DSB repair; the participation is captured by NHEJ rather than a chromosome organization role. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0051402 neuron apoptotic process	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS from mouse Lig4 for neuron apoptotic process. Reason: LIG4 does not take part in apoptosis; its loss causes apoptosis indirectly through unrepaired DSBs. Supporting Evidence: PMID:9889105 targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system
GO:0070419 nonhomologous end joining complex	IDA PMID:20383123 Ku is a 5'-dRP/AP lyase that excises nucleotide damage near ...	ACCEPT	Summary: Ku 5'-dRP/AP lyase study using purified core NHEJ factors including XRCC4-LIG4. Reason: LIG4/XRCC4 is a core subunit of the NHEJ complex assembled on DNA ends. Supporting Evidence: PMID:20383123 purified human NHEJ core factors (Ku, DNA-PKcs, XLF/Cernunnos, and XRCC4-LigaseIV) PMID:34352203 we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA
GO:0070419 nonhomologous end joining complex	IDA PMID:25941166 XLS (c9orf142) is a new component of mammalian DNA double-st...	ACCEPT	Summary: Affinity purification of DNA-PKcs co-purifies all core NHEJ factors including LIG4. Reason: Direct evidence of LIG4 in the NHEJ complex. Supporting Evidence: PMID:25941166 DNA-PKcs co-purifies with all known core NHEJ factors
GO:0071479 cellular response to ionizing radiation	IGI PMID:29463814 LEM-3 is a midbody-tethered DNA nuclease that resolves chrom...	REMOVE	Summary: IGI to C. elegans LEM-3 (G5EGA3) for cellular response to ionizing radiation. The paper is a C. elegans study that combines lem-3 with lig-4 null alleles. Reason: The abstract and full text state that the work is in C. elegans embryos, and the genetic interaction is between worm lem-3 and worm lig-4. No human LIG4 experiment is reported, so the annotation belongs to C. elegans lig-4, not human LIG4. Supporting Evidence: PMID:29463814 Using C. elegans embryos we show that the LEM-3/Ankle1 nuclease defines a previously undescribed genome integrity mechanism
GO:0071897 DNA biosynthetic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro-based DNA biosynthetic process. Reason: LIG4 joins DNA ends in NHEJ; it has no role in DNA synthesis or replication, and the generic ligase-domain mapping over-reaches. Supporting Evidence: PMID:9809069 Hence, DNA ligase IV is the activity responsible for the ligation step in NHEJ and in V(D)J recombination.
GO:0075713 establishment of integrated proviral latency	TAS Reactome:R-HSA-162592	MARK AS OVER ANNOTATED	Summary: Reactome HIV pathway placing LIG4 in 2-LTR circle formation of unintegrated viral DNA. Reason: Host NHEJ (Ku, XRCC4, LIG4) circularises unintegrated viral DNA, a dead-end product; LIG4 does not establish integrated proviral latency. Supporting Evidence: Reactome:R-HSA-175258 Viral DNA that does not become integrated can undergo another fate, which is to have the two viral DNA ends joined together to form a 2-LTR circle.
GO:0097680 double-strand break repair via classical nonhomologous end joining	IMP PMID:24837021 DNA ligase III and DNA ligase IV carry out genetically disti...	ACCEPT	Summary: In human somatic cells most end-joining events depend on LIG4, including a Ku-independent LIG4 pathway. Reason: LIG4 is the ligase of classical NHEJ; this is the most specific correct process term. Supporting Evidence: PMID:24837021 Most unexpectedly, however, the majority of EJing events remained LIGIV-dependent. PMID:29980672 DNA ligase IV (LigIV) performs the final DNA nick-sealing step of classical nonhomologous end-joining
GO:2001252 positive regulation of chromosome organization	IMP PMID:23275564 Human LIGIV is synthetically lethal with the loss of Rad54B-...	MARK AS OVER ANNOTATED	Summary: LIG4 is required for chromosome fusions induced by TRF2 dysfunction. Reason: LIG4 does not regulate chromosome organization; it ligates deprotected telomeres by classical NHEJ, producing fusions. The participation is captured by NHEJ and the telomeric-region location. Supporting Evidence: PMID:23275564 LIGIV is differentially required for certain chromosome fusion events induced by telomere dysfunction

Gene Description

Existing Annotations Review

Core Functions

Ligase of classical NHEJ. In complex with XRCC4, and within the Ku/DNA-PKcs/XLF synaptic complex, LIG4 seals double-strand break ends, including the coding and signal joints of V(D)J recombination and deprotected telomere ends.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

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