{"gene":"LIG4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2004,"finding":"Hypomorphic mutations in DNA ligase IV (LIG4) cause LIG4 syndrome; residual ligase activity correlates with severity of clinical features including immunodeficiency and developmental delay, establishing LIG4 as an essential component of DNA non-homologous end-joining (NHEJ).","method":"Biochemical analysis of recombinant mutant proteins, clinical genotype-phenotype correlation","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein activity assays combined with genotype-phenotype analysis in multiple patients, single lab","pmids":["15279811","15333585"],"is_preprint":false},{"year":2004,"finding":"Examination of recombinant mutant LIG4 proteins from LIG4 syndrome patients showed that two linked polymorphisms reduce DNA ligase IV activity approximately 2-fold; when combined with the R278H mutation, activity is reduced to levels comparable to other LIG4 syndrome patients with immunodeficiency and developmental delay. A nuclear localization signal was also identified in LIG4, and residues required for adenylation were mapped.","method":"Recombinant mutant protein activity assays, complementation analysis, site-directed mutagenesis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with multiple mutant proteins, mutagenesis identifying NLS and adenylation sites, single lab but multiple orthogonal methods","pmids":["15333585"],"is_preprint":false},{"year":2005,"finding":"A LIG4 mutation (distinct from those in LIG4 syndrome) causes T-B-NK+ SCID with a severe block in precursor B cell differentiation; residual D(H)-J(H) junctions show extensive nucleotide deletions consistent with prolonged exonuclease activity during delayed ligation, demonstrating LIG4's direct role in V(D)J recombination end-joining.","method":"Genetic analysis, PCR analysis of V(D)J junctions, radiosensitivity assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular analysis of recombination junctions in patient cells with defined LIG4 mutation, single case but multiple methods","pmids":["16357942"],"is_preprint":false},{"year":2007,"finding":"DNA ligase IV (LIG4/Dnl4) interacts directly with XRCC4 (Lif1 in yeast) via a stable coiled-coil-mediated interaction; XLF (Cernunnos) also interacts with both XRCC4 and LIG4, but by different protein domains (globular head of XRCC4 contacts N- and C-terminal domains of XLF/Nej1 respectively), establishing the protein interaction architecture of the NHEJ ligation complex.","method":"Yeast two-hybrid, co-precipitation assays, domain mapping","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-precipitation and two-hybrid in yeast, two orthogonal methods but single lab","pmids":["17567543"],"is_preprint":false},{"year":2010,"finding":"Knock-in mice homozygous for the Lig4 R278H mutation recapitulate LIG4 syndrome: growth retardation, severe T and B cell developmental block, restricted lymphocyte repertoire, genomic instability, and high thymic tumor rate, confirming that reduced LIG4 activity impairs V(D)J recombination and lymphocyte development in vivo.","method":"Knock-in mouse model, flow cytometry, irradiation sensitivity assays, tumor analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in model with multiple orthogonal phenotypic readouts, genetically defined allele","pmids":["20133615"],"is_preprint":false},{"year":2016,"finding":"LIG4 is a direct transcriptional target of β-catenin; Wnt signalling upregulates LIG4 expression, which in turn enhances NHEJ repair in colorectal cancer cells and intestinal stem cells, providing the molecular mechanism for Wnt-induced radioresistance. Blocking LIG4 sensitizes CRC cells to radiation.","method":"β-catenin ChIP, LIG4 promoter reporter assays, LIG4 knockdown/overexpression with NHEJ reporter assays and clonogenic survival, conditional mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct β-catenin binding to LIG4 promoter, functional NHEJ assays, in vivo mouse model, multiple orthogonal methods","pmids":["27009971"],"is_preprint":false},{"year":2017,"finding":"DNA ligase IV (LIG4) is essential for NHEJ-mediated random integration of foreign DNA in human cells; dual loss of LIG4 and DNA polymerase θ (POLQ) abolishes random integration, revealing that NHEJ (via LIG4) and theta-mediated end joining are the two homology-independent integration routes.","method":"CRISPR/Cas9 double-knockout cell lines, gene targeting assays, integration frequency measurement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double-KO human cells with quantitative integration assays, functional epistasis between LIG4 and POLQ","pmids":["28695890"],"is_preprint":false},{"year":2024,"finding":"SMYD3 is recruited to DNA damage sites in a PARP1-dependent manner and directly methylates LIG4; this methylation triggers sequential assembly of the LIG4/XRCC4/XLF complex, promoting NHEJ repair. SMYD3 depletion compromises NHEJ and sensitizes endometrial cancer cells to radiation.","method":"Co-immunoprecipitation, in vitro methylation assay, NHEJ reporter assays, in vivo xenograft model, SMYD3 inhibitor treatment","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro methylation with functional NHEJ readout, in vivo model, single lab","pmids":["38191478"],"is_preprint":false},{"year":2025,"finding":"LIG4 catalyzes the ligation step in ecDNA (extrachromosomal circular DNA) biogenesis in Drosophila and mammalian cells; ecDNA from patient tumors harbors junction sites with a LIG4 signature. Disrupting LIG4 impairs ecDNA production and ecDNA-mediated adaptation to chemotherapy and targeted therapies.","method":"Genome-wide CRISPR screen, LIG4 knockout cell lines, ecDNA junction sequencing, drug resistance assays, Drosophila genetic model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen, functional KO, junction sequencing showing LIG4 signature, multi-organism validation","pmids":["41811450","40027615"],"is_preprint":false},{"year":2025,"finding":"Catalytically inactive Lig4 (point mutation at catalytic site) partially rescues the embryonic lethality and DNA repair defects of Lig4-null mice, demonstrating a structural scaffolding role for Lig4 in maintaining the NHEJ repair complex independent of its catalytic activity. Nuclear Lig3 is recruited to NHEJ complexes to perform ligation in the presence (but not activity) of Lig4; mice lacking both nuclear Lig3 and catalytically inactive Lig4 are embryonic lethal.","method":"Knock-in mouse model with catalytic-site point mutation, nuclear Lig3-deficient mouse strain, genetic crosses, lymphocyte development analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo catalytic-dead knock-in mouse plus epistatic double-mutant lethality, multiple orthogonal methods demonstrating structural versus catalytic Lig4 functions","pmids":["39673806"],"is_preprint":false},{"year":2025,"finding":"PIPKIγ directly interacts with LIG4 and strengthens LIG4's interaction with XRCC4, facilitating LIG4 nuclear translocation and NHEJ repair efficiency, thereby promoting radioresistance in triple-negative breast cancer cells.","method":"Co-immunoprecipitation, pull-down assays, nuclear fractionation, NHEJ reporter assays, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and pull-down demonstrating direct PIPKIγ-LIG4 interaction, nuclear translocation assay, functional NHEJ readout, single lab","pmids":["40744919"],"is_preprint":false},{"year":2025,"finding":"Lactate directly binds XRCC4 at residues Y66, E55, and S110, strengthening the XRCC4-LIG4 association independently of protein lactylation, thereby enhancing NHEJ efficiency and chemoresistance in ovarian cancer cells.","method":"Co-immunoprecipitation, pull-down assays, site-directed mutagenesis of XRCC4, NHEJ reporter assay, molecular docking, in vivo mouse model","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, in vitro binding, and functional NHEJ assay, single lab multiple orthogonal methods","pmids":["41462961"],"is_preprint":false},{"year":2024,"finding":"RAP1, when bound to TRF2, establishes interactions with KU and DNA that prevent DNA-PK from recruiting LIG4, thereby directly repressing chromosome end joining at telomeres. This was shown biochemically and by cryo-EM structural analysis.","method":"Cryo-electron microscopy, biochemical reconstitution, cell-based telomere fusion assays","journal":"bioRxiv (preprint)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus biochemical reconstitution showing RAP1 prevents LIG4 recruitment to DNA-PK, single lab but two orthogonal high-quality methods","pmids":[],"is_preprint":true},{"year":2013,"finding":"A LIG4 mutation (p.S205LfsX29) that eliminates the nuclear localization signal functions as a null mutation, and a second mutation (p.K635RfsX10) lacking the C-terminal XRCC4-binding region also abrogates LIG4 stability and activity, demonstrating that the NLS and the XRCC4-binding C-terminal domain are each required for LIG4 function.","method":"Genetic analysis of patient mutations, functional inference from domain ablation, clinical phenotyping","journal":"Human mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — domain function inferred from patient null mutations without direct biochemical reconstitution; single case","pmids":["24027040"],"is_preprint":false},{"year":2025,"finding":"Knockdown of LIG4 (along with KU80) abolishes SOX2-mediated in vivo glia-to-neuron reprogramming in the adult CNS, placing LIG4-dependent NHEJ as required for this reprogramming process; p53 knockdown restores reprogramming in PRKDC-deficient mice, indicating LIG4/NHEJ acts upstream of p53 in this context.","method":"In vivo knockdown in mice, PRKDC knockout, p53 knockdown rescue, neural reprogramming assay","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vivo knockdown with functional readout but LIG4 is one of several NHEJ components tested; preprint, single study","pmids":[],"is_preprint":true}],"current_model":"DNA ligase IV (LIG4) is the essential ATP-dependent ligase that executes the final nick-sealing step of classical non-homologous end joining (NHEJ), functioning in a complex with XRCC4 and XLF; it requires its C-terminal XRCC4-binding domain for stability and nuclear localization, plays a structural scaffolding role in the NHEJ complex independent of catalysis (with nuclear LIG4 recruiting Lig3 to complete ligation when LIG4 is catalytically inactive), is post-translationally regulated by SMYD3-mediated methylation that triggers LIG4/XRCC4/XLF complex assembly, is directly transcriptionally activated by β-catenin/Wnt signaling to promote radioresistance, mediates extrachromosomal circular DNA (ecDNA) biogenesis in cancer cells, and is prevented from acting at telomeres by a RAP1-TRF2-DNA-PK complex that blocks LIG4 recruitment."},"narrative":{"mechanistic_narrative":"LIG4 encodes the ATP-dependent DNA ligase that executes the final nick-sealing step of classical non-homologous end joining (NHEJ), the dominant pathway for repairing DNA double-strand breaks and for joining coding and signal ends during V(D)J recombination [PMID:15279811, PMID:15333585, PMID:16357942]. It functions as a stable complex with XRCC4, contacting XRCC4 through a coiled-coil-mediated interaction at its C-terminal domain, while XLF (Cernunnos) bridges to both partners through distinct domains to build the ligation module of the NHEJ machinery [PMID:17567543]. LIG4 function depends on a defined nuclear localization signal and on its C-terminal XRCC4-binding region, both of which are required for nuclear targeting, protein stability, and activity [PMID:15333585, PMID:24027040]. Hypomorphic LIG4 mutations that reduce residual ligase activity cause LIG4 syndrome (immunodeficiency and developmental delay) and a form of T-B-NK+ SCID, with residual activity scaling to clinical severity; knock-in of the R278H allele in mice recapitulates the growth retardation, lymphocyte developmental block, genomic instability and tumor predisposition [PMID:15279811, PMID:15333585, PMID:16357942, PMID:20133615]. Beyond catalysis, LIG4 plays a structural scaffolding role within the NHEJ complex: catalytically inactive Lig4 partially rescues Lig4-null lethality and repair defects by maintaining the complex and permitting nuclear Lig3 to complete ligation, with loss of both being embryonic lethal [PMID:39673806]. LIG4 activity is gated by multiple inputs—SMYD3-mediated methylation triggers assembly of the LIG4/XRCC4/XLF complex [PMID:38191478], PIPKIγ and lactate-bound XRCC4 each strengthen the LIG4–XRCC4 association to boost repair [PMID:40744919, PMID:41462961], and β-catenin/Wnt signaling directly transcriptionally activates LIG4 to drive radioresistance [PMID:27009971]. LIG4-dependent end joining also underlies homology-independent random integration of foreign DNA (alongside POLQ) [PMID:28695890] and the ligation step of extrachromosomal circular DNA (ecDNA) biogenesis in cancer [PMID:41811450, PMID:40027615]. At chromosome ends, a RAP1–TRF2 complex blocks DNA-PK from recruiting LIG4, repressing telomere fusion.","teleology":[{"year":2004,"claim":"Establishing LIG4 as an essential NHEJ component required showing that reduced ligase activity, rather than complete loss, underlies a human disease and scales with phenotype severity.","evidence":"Biochemical activity assays of recombinant LIG4 syndrome mutant proteins with genotype-phenotype correlation, plus mutagenesis mapping an NLS and adenylation residues","pmids":["15279811","15333585"],"confidence":"High","gaps":["Did not resolve how partial activity loss differentially affects V(D)J versus general DSB repair","Structural basis of how mutations impair the enzyme not defined"]},{"year":2005,"claim":"Directly tying LIG4 to V(D)J recombination clarified the immunodeficiency mechanism, showing that delayed ligation permits aberrant exonucleolytic processing of recombination junctions.","evidence":"Molecular analysis of D(H)-J(H) junctions and radiosensitivity in patient cells carrying a distinct LIG4 mutation causing T-B-NK+ SCID","pmids":["16357942"],"confidence":"Medium","gaps":["Single patient case","Did not establish the kinetic step at which ligation is rate-limiting"]},{"year":2007,"claim":"Defining the protein architecture of the ligation complex answered how LIG4 is organized with its partners during end joining.","evidence":"Yeast two-hybrid and reciprocal co-precipitation with domain mapping of LIG4(Dnl4)-XRCC4(Lif1) and XLF interactions","pmids":["17567543"],"confidence":"Medium","gaps":["Interactions characterized largely in yeast orthologs","Stoichiometry and higher-order filament assembly not resolved here"]},{"year":2010,"claim":"An in vivo model was needed to confirm that the human R278H hypomorph causally produces the LIG4 syndrome phenotype.","evidence":"Lig4 R278H knock-in mice analyzed by flow cytometry, irradiation sensitivity, and tumor scoring","pmids":["20133615"],"confidence":"High","gaps":["Does not separate developmental from repair-specific contributions","Mechanism of thymic tumor predisposition not dissected"]},{"year":2016,"claim":"Identifying LIG4 as a direct β-catenin target explained how an oncogenic signaling pathway controls DSB repair capacity and radioresistance.","evidence":"β-catenin ChIP, LIG4 promoter reporters, NHEJ reporter and clonogenic survival assays with knockdown/overexpression, and a conditional mouse model","pmids":["27009971"],"confidence":"High","gaps":["Other transcriptional inputs to LIG4 not mapped","Did not address whether Wnt regulates LIG4 protein turnover"]},{"year":2017,"claim":"Defining the homology-independent integration routes established LIG4/NHEJ and POLQ as the two pathways mediating random foreign-DNA insertion.","evidence":"CRISPR/Cas9 LIG4/POLQ double-knockout human cells with quantitative integration assays demonstrating epistasis","pmids":["28695890"],"confidence":"High","gaps":["Does not detail junction architecture of LIG4-mediated integrants","Relative contribution in primary cells unaddressed"]},{"year":2024,"claim":"Discovery of SMYD3-mediated LIG4 methylation revealed a post-translational trigger for assembly of the ligation complex.","evidence":"Co-IP, in vitro methylation, NHEJ reporter assays, and xenograft/SMYD3-inhibitor studies in endometrial cancer cells","pmids":["38191478"],"confidence":"Medium","gaps":["Methylated residues and their structural effect not mapped","Single lab, single cancer context"]},{"year":2025,"claim":"A catalytic-dead knock-in established that LIG4 has a structural scaffolding role distinct from its enzymatic activity, with nuclear Lig3 able to perform ligation when LIG4 is present but inactive.","evidence":"Lig4 catalytic-site point-mutant knock-in mice crossed to nuclear Lig3-deficient strain, with lymphocyte development and lethality analysis","pmids":["39673806"],"confidence":"High","gaps":["Molecular interface enabling Lig3 substitution not defined","Extent of scaffolding rescue across cell types unclear"]},{"year":2025,"claim":"Showing LIG4 catalyzes ecDNA junction ligation linked NHEJ to a cancer genome-amplification mechanism and therapy adaptation.","evidence":"Genome-wide CRISPR screen, LIG4 knockouts, ecDNA junction sequencing revealing a LIG4 signature, and drug-resistance assays across Drosophila and mammalian cells","pmids":["41811450","40027615"],"confidence":"High","gaps":["Upstream events generating the circular precursors not defined","Whether LIG4 ecDNA role requires the canonical XRCC4/XLF complex untested here"]},{"year":2025,"claim":"Identifying PIPKIγ and lactate as enhancers of the LIG4-XRCC4 interaction revealed additional regulatory inputs that tune NHEJ-driven therapy resistance.","evidence":"Co-IP, pull-down, nuclear fractionation, XRCC4 mutagenesis/docking, and NHEJ reporter and xenograft assays in breast and ovarian cancer cells","pmids":["40744919","41462961"],"confidence":"Medium","gaps":["Mechanistic detail of how interaction strengthening accelerates ligation unresolved","Physiological versus pathological relevance of these inputs unclear"]},{"year":2024,"claim":"Structural and biochemical work explained how telomeres avoid LIG4-mediated fusion, by RAP1-TRF2 blocking DNA-PK recruitment of LIG4.","evidence":"Cryo-EM, biochemical reconstitution, and telomere fusion assays (preprint)","pmids":[],"confidence":"High","gaps":["Preprint, not peer-reviewed","Whether the block is overcome under pathological telomere deprotection in vivo not addressed"]},{"year":2025,"claim":"A developmental role was probed by testing whether LIG4/NHEJ is required for in vivo cellular reprogramming.","evidence":"In vivo LIG4/KU80 knockdown with PRKDC knockout and p53-knockdown rescue in a SOX2 glia-to-neuron reprogramming assay (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint and LIG4 is one of several NHEJ components tested, not isolated","Direct requirement for LIG4 catalytic activity not established"]},{"year":null,"claim":"How LIG4's many regulatory inputs (methylation, transcriptional control, interaction modifiers, and telomeric exclusion) are coordinated to determine when and where ligation proceeds remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating post-translational and partner-mediated regulation","Hierarchy among Wnt, SMYD3, PIPKIγ and lactate inputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,13,10]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,6,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4]}],"complexes":["LIG4/XRCC4/XLF NHEJ ligation complex"],"partners":["XRCC4","XLF","SMYD3","PIPKIΓ","LIG3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49917","full_name":"DNA ligase 4","aliases":["DNA ligase IV","Polydeoxyribonucleotide synthase [ATP] 4"],"length_aa":911,"mass_kda":104.0,"function":"DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination (PubMed:12517771, PubMed:17290226, PubMed:23523427, PubMed:29980672, PubMed:33586762, PubMed:8798671, PubMed:9242410, PubMed:9809069). Catalyzes the NHEJ ligation step of the broken DNA during DSB repair by resealing the DNA breaks after the gap filling is completed (PubMed:12517771, PubMed:17290226, PubMed:9242410, PubMed:9809069). Joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction (PubMed:12517771, PubMed:17290226, PubMed:9242410, PubMed:9809069). LIG4 is mechanistically flexible: it can ligate nicks as well as compatible DNA overhangs alone, while in the presence of XRCC4, it can ligate ends with 2-nucleotides (nt) microhomology and 1-nt gaps (PubMed:17290226). Forms a subcomplex with XRCC4; the LIG4-XRCC4 subcomplex is responsible for the NHEJ ligation step and XRCC4 enhances the joining activity of LIG4 (PubMed:9242410, PubMed:9809069). Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends (PubMed:10854421). LIG4 regulates nuclear localization of XRCC4 (PubMed:24984242)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P49917/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LIG4","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK1A1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LIG4","total_profiled":1310},"omim":[{"mim_id":"616541","title":"SHORT STATURE, MICROCEPHALY, AND ENDOCRINE DYSFUNCTION; SSMED","url":"https://www.omim.org/entry/616541"},{"mim_id":"616315","title":"PAXX NONHOMOLOGOUS END JOINING FACTOR; PAXX","url":"https://www.omim.org/entry/616315"},{"mim_id":"611291","title":"IMMUNODEFICIENCY 124, SEVERE COMBINED; IMD124","url":"https://www.omim.org/entry/611291"},{"mim_id":"611290","title":"NONHOMOLOGOUS END-JOINING FACTOR 1; NHEJ1","url":"https://www.omim.org/entry/611290"},{"mim_id":"606593","title":"LIG4 SYNDROME","url":"https://www.omim.org/entry/606593"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LIG4"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P49917","domains":[{"cath_id":"1.10.3260.10","chopping":"9-211","consensus_level":"medium","plddt":92.3521,"start":9,"end":211},{"cath_id":"3.30.470.30","chopping":"249-450","consensus_level":"high","plddt":92.7756,"start":249,"end":450},{"cath_id":"2.40.50.140","chopping":"461-604","consensus_level":"high","plddt":92.9608,"start":461,"end":604},{"cath_id":"3.40.50.10190","chopping":"641-769","consensus_level":"high","plddt":85.3916,"start":641,"end":769},{"cath_id":"3.40.50.10190","chopping":"790-907","consensus_level":"high","plddt":86.5578,"start":790,"end":907}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49917","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49917-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49917-F1-predicted_aligned_error_v6.png","plddt_mean":88.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LIG4","jax_strain_url":"https://www.jax.org/strain/search?query=LIG4"},"sequence":{"accession":"P49917","fasta_url":"https://rest.uniprot.org/uniprotkb/P49917.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49917/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49917"}},"corpus_meta":[{"pmid":"15279811","id":"PMC_15279811","title":"An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome.","date":"2004","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/15279811","citation_count":144,"is_preprint":false},{"pmid":"15609317","id":"PMC_15609317","title":"Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk.","date":"2005","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15609317","citation_count":137,"is_preprint":false},{"pmid":"16357942","id":"PMC_16357942","title":"A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation.","date":"2005","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/16357942","citation_count":137,"is_preprint":false},{"pmid":"18282727","id":"PMC_18282727","title":"A defect of LigD (human Lig4 homolog) for nonhomologous end joining significantly 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ligase IV (LIG4) cause LIG4 syndrome; residual ligase activity correlates with severity of clinical features including immunodeficiency and developmental delay, establishing LIG4 as an essential component of DNA non-homologous end-joining (NHEJ).\",\n      \"method\": \"Biochemical analysis of recombinant mutant proteins, clinical genotype-phenotype correlation\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein activity assays combined with genotype-phenotype analysis in multiple patients, single lab\",\n      \"pmids\": [\"15279811\", \"15333585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Examination of recombinant mutant LIG4 proteins from LIG4 syndrome patients showed that two linked polymorphisms reduce DNA ligase IV activity approximately 2-fold; when combined with the R278H mutation, activity is reduced to levels comparable to other LIG4 syndrome patients with immunodeficiency and developmental delay. A nuclear localization signal was also identified in LIG4, and residues required for adenylation were mapped.\",\n      \"method\": \"Recombinant mutant protein activity assays, complementation analysis, site-directed mutagenesis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with multiple mutant proteins, mutagenesis identifying NLS and adenylation sites, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15333585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A LIG4 mutation (distinct from those in LIG4 syndrome) causes T-B-NK+ SCID with a severe block in precursor B cell differentiation; residual D(H)-J(H) junctions show extensive nucleotide deletions consistent with prolonged exonuclease activity during delayed ligation, demonstrating LIG4's direct role in V(D)J recombination end-joining.\",\n      \"method\": \"Genetic analysis, PCR analysis of V(D)J junctions, radiosensitivity assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular analysis of recombination junctions in patient cells with defined LIG4 mutation, single case but multiple methods\",\n      \"pmids\": [\"16357942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DNA ligase IV (LIG4/Dnl4) interacts directly with XRCC4 (Lif1 in yeast) via a stable coiled-coil-mediated interaction; XLF (Cernunnos) also interacts with both XRCC4 and LIG4, but by different protein domains (globular head of XRCC4 contacts N- and C-terminal domains of XLF/Nej1 respectively), establishing the protein interaction architecture of the NHEJ ligation complex.\",\n      \"method\": \"Yeast two-hybrid, co-precipitation assays, domain mapping\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-precipitation and two-hybrid in yeast, two orthogonal methods but single lab\",\n      \"pmids\": [\"17567543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Knock-in mice homozygous for the Lig4 R278H mutation recapitulate LIG4 syndrome: growth retardation, severe T and B cell developmental block, restricted lymphocyte repertoire, genomic instability, and high thymic tumor rate, confirming that reduced LIG4 activity impairs V(D)J recombination and lymphocyte development in vivo.\",\n      \"method\": \"Knock-in mouse model, flow cytometry, irradiation sensitivity assays, tumor analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in model with multiple orthogonal phenotypic readouts, genetically defined allele\",\n      \"pmids\": [\"20133615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LIG4 is a direct transcriptional target of β-catenin; Wnt signalling upregulates LIG4 expression, which in turn enhances NHEJ repair in colorectal cancer cells and intestinal stem cells, providing the molecular mechanism for Wnt-induced radioresistance. Blocking LIG4 sensitizes CRC cells to radiation.\",\n      \"method\": \"β-catenin ChIP, LIG4 promoter reporter assays, LIG4 knockdown/overexpression with NHEJ reporter assays and clonogenic survival, conditional mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct β-catenin binding to LIG4 promoter, functional NHEJ assays, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"27009971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DNA ligase IV (LIG4) is essential for NHEJ-mediated random integration of foreign DNA in human cells; dual loss of LIG4 and DNA polymerase θ (POLQ) abolishes random integration, revealing that NHEJ (via LIG4) and theta-mediated end joining are the two homology-independent integration routes.\",\n      \"method\": \"CRISPR/Cas9 double-knockout cell lines, gene targeting assays, integration frequency measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double-KO human cells with quantitative integration assays, functional epistasis between LIG4 and POLQ\",\n      \"pmids\": [\"28695890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD3 is recruited to DNA damage sites in a PARP1-dependent manner and directly methylates LIG4; this methylation triggers sequential assembly of the LIG4/XRCC4/XLF complex, promoting NHEJ repair. SMYD3 depletion compromises NHEJ and sensitizes endometrial cancer cells to radiation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, NHEJ reporter assays, in vivo xenograft model, SMYD3 inhibitor treatment\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro methylation with functional NHEJ readout, in vivo model, single lab\",\n      \"pmids\": [\"38191478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LIG4 catalyzes the ligation step in ecDNA (extrachromosomal circular DNA) biogenesis in Drosophila and mammalian cells; ecDNA from patient tumors harbors junction sites with a LIG4 signature. Disrupting LIG4 impairs ecDNA production and ecDNA-mediated adaptation to chemotherapy and targeted therapies.\",\n      \"method\": \"Genome-wide CRISPR screen, LIG4 knockout cell lines, ecDNA junction sequencing, drug resistance assays, Drosophila genetic model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen, functional KO, junction sequencing showing LIG4 signature, multi-organism validation\",\n      \"pmids\": [\"41811450\", \"40027615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Catalytically inactive Lig4 (point mutation at catalytic site) partially rescues the embryonic lethality and DNA repair defects of Lig4-null mice, demonstrating a structural scaffolding role for Lig4 in maintaining the NHEJ repair complex independent of its catalytic activity. Nuclear Lig3 is recruited to NHEJ complexes to perform ligation in the presence (but not activity) of Lig4; mice lacking both nuclear Lig3 and catalytically inactive Lig4 are embryonic lethal.\",\n      \"method\": \"Knock-in mouse model with catalytic-site point mutation, nuclear Lig3-deficient mouse strain, genetic crosses, lymphocyte development analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo catalytic-dead knock-in mouse plus epistatic double-mutant lethality, multiple orthogonal methods demonstrating structural versus catalytic Lig4 functions\",\n      \"pmids\": [\"39673806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIPKIγ directly interacts with LIG4 and strengthens LIG4's interaction with XRCC4, facilitating LIG4 nuclear translocation and NHEJ repair efficiency, thereby promoting radioresistance in triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, nuclear fractionation, NHEJ reporter assays, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and pull-down demonstrating direct PIPKIγ-LIG4 interaction, nuclear translocation assay, functional NHEJ readout, single lab\",\n      \"pmids\": [\"40744919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lactate directly binds XRCC4 at residues Y66, E55, and S110, strengthening the XRCC4-LIG4 association independently of protein lactylation, thereby enhancing NHEJ efficiency and chemoresistance in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, site-directed mutagenesis of XRCC4, NHEJ reporter assay, molecular docking, in vivo mouse model\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, in vitro binding, and functional NHEJ assay, single lab multiple orthogonal methods\",\n      \"pmids\": [\"41462961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAP1, when bound to TRF2, establishes interactions with KU and DNA that prevent DNA-PK from recruiting LIG4, thereby directly repressing chromosome end joining at telomeres. This was shown biochemically and by cryo-EM structural analysis.\",\n      \"method\": \"Cryo-electron microscopy, biochemical reconstitution, cell-based telomere fusion assays\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus biochemical reconstitution showing RAP1 prevents LIG4 recruitment to DNA-PK, single lab but two orthogonal high-quality methods\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A LIG4 mutation (p.S205LfsX29) that eliminates the nuclear localization signal functions as a null mutation, and a second mutation (p.K635RfsX10) lacking the C-terminal XRCC4-binding region also abrogates LIG4 stability and activity, demonstrating that the NLS and the XRCC4-binding C-terminal domain are each required for LIG4 function.\",\n      \"method\": \"Genetic analysis of patient mutations, functional inference from domain ablation, clinical phenotyping\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — domain function inferred from patient null mutations without direct biochemical reconstitution; single case\",\n      \"pmids\": [\"24027040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of LIG4 (along with KU80) abolishes SOX2-mediated in vivo glia-to-neuron reprogramming in the adult CNS, placing LIG4-dependent NHEJ as required for this reprogramming process; p53 knockdown restores reprogramming in PRKDC-deficient mice, indicating LIG4/NHEJ acts upstream of p53 in this context.\",\n      \"method\": \"In vivo knockdown in mice, PRKDC knockout, p53 knockdown rescue, neural reprogramming assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vivo knockdown with functional readout but LIG4 is one of several NHEJ components tested; preprint, single study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DNA ligase IV (LIG4) is the essential ATP-dependent ligase that executes the final nick-sealing step of classical non-homologous end joining (NHEJ), functioning in a complex with XRCC4 and XLF; it requires its C-terminal XRCC4-binding domain for stability and nuclear localization, plays a structural scaffolding role in the NHEJ complex independent of catalysis (with nuclear LIG4 recruiting Lig3 to complete ligation when LIG4 is catalytically inactive), is post-translationally regulated by SMYD3-mediated methylation that triggers LIG4/XRCC4/XLF complex assembly, is directly transcriptionally activated by β-catenin/Wnt signaling to promote radioresistance, mediates extrachromosomal circular DNA (ecDNA) biogenesis in cancer cells, and is prevented from acting at telomeres by a RAP1-TRF2-DNA-PK complex that blocks LIG4 recruitment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIG4 encodes the ATP-dependent DNA ligase that executes the final nick-sealing step of classical non-homologous end joining (NHEJ), the dominant pathway for repairing DNA double-strand breaks and for joining coding and signal ends during V(D)J recombination [#0, #2]. It functions as a stable complex with XRCC4, contacting XRCC4 through a coiled-coil-mediated interaction at its C-terminal domain, while XLF (Cernunnos) bridges to both partners through distinct domains to build the ligation module of the NHEJ machinery [#3]. LIG4 function depends on a defined nuclear localization signal and on its C-terminal XRCC4-binding region, both of which are required for nuclear targeting, protein stability, and activity [#1, #13]. Hypomorphic LIG4 mutations that reduce residual ligase activity cause LIG4 syndrome (immunodeficiency and developmental delay) and a form of T-B-NK+ SCID, with residual activity scaling to clinical severity; knock-in of the R278H allele in mice recapitulates the growth retardation, lymphocyte developmental block, genomic instability and tumor predisposition [#0, #2, #4]. Beyond catalysis, LIG4 plays a structural scaffolding role within the NHEJ complex: catalytically inactive Lig4 partially rescues Lig4-null lethality and repair defects by maintaining the complex and permitting nuclear Lig3 to complete ligation, with loss of both being embryonic lethal [#9]. LIG4 activity is gated by multiple inputs—SMYD3-mediated methylation triggers assembly of the LIG4/XRCC4/XLF complex [#7], PIPKIγ and lactate-bound XRCC4 each strengthen the LIG4–XRCC4 association to boost repair [#10, #11], and β-catenin/Wnt signaling directly transcriptionally activates LIG4 to drive radioresistance [#5]. LIG4-dependent end joining also underlies homology-independent random integration of foreign DNA (alongside POLQ) [#6] and the ligation step of extrachromosomal circular DNA (ecDNA) biogenesis in cancer [#8]. At chromosome ends, a RAP1–TRF2 complex blocks DNA-PK from recruiting LIG4, repressing telomere fusion [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing LIG4 as an essential NHEJ component required showing that reduced ligase activity, rather than complete loss, underlies a human disease and scales with phenotype severity.\",\n      \"evidence\": \"Biochemical activity assays of recombinant LIG4 syndrome mutant proteins with genotype-phenotype correlation, plus mutagenesis mapping an NLS and adenylation residues\",\n      \"pmids\": [\"15279811\", \"15333585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how partial activity loss differentially affects V(D)J versus general DSB repair\", \"Structural basis of how mutations impair the enzyme not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Directly tying LIG4 to V(D)J recombination clarified the immunodeficiency mechanism, showing that delayed ligation permits aberrant exonucleolytic processing of recombination junctions.\",\n      \"evidence\": \"Molecular analysis of D(H)-J(H) junctions and radiosensitivity in patient cells carrying a distinct LIG4 mutation causing T-B-NK+ SCID\",\n      \"pmids\": [\"16357942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"Did not establish the kinetic step at which ligation is rate-limiting\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the protein architecture of the ligation complex answered how LIG4 is organized with its partners during end joining.\",\n      \"evidence\": \"Yeast two-hybrid and reciprocal co-precipitation with domain mapping of LIG4(Dnl4)-XRCC4(Lif1) and XLF interactions\",\n      \"pmids\": [\"17567543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactions characterized largely in yeast orthologs\", \"Stoichiometry and higher-order filament assembly not resolved here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"An in vivo model was needed to confirm that the human R278H hypomorph causally produces the LIG4 syndrome phenotype.\",\n      \"evidence\": \"Lig4 R278H knock-in mice analyzed by flow cytometry, irradiation sensitivity, and tumor scoring\",\n      \"pmids\": [\"20133615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate developmental from repair-specific contributions\", \"Mechanism of thymic tumor predisposition not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying LIG4 as a direct β-catenin target explained how an oncogenic signaling pathway controls DSB repair capacity and radioresistance.\",\n      \"evidence\": \"β-catenin ChIP, LIG4 promoter reporters, NHEJ reporter and clonogenic survival assays with knockdown/overexpression, and a conditional mouse model\",\n      \"pmids\": [\"27009971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional inputs to LIG4 not mapped\", \"Did not address whether Wnt regulates LIG4 protein turnover\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining the homology-independent integration routes established LIG4/NHEJ and POLQ as the two pathways mediating random foreign-DNA insertion.\",\n      \"evidence\": \"CRISPR/Cas9 LIG4/POLQ double-knockout human cells with quantitative integration assays demonstrating epistasis\",\n      \"pmids\": [\"28695890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not detail junction architecture of LIG4-mediated integrants\", \"Relative contribution in primary cells unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of SMYD3-mediated LIG4 methylation revealed a post-translational trigger for assembly of the ligation complex.\",\n      \"evidence\": \"Co-IP, in vitro methylation, NHEJ reporter assays, and xenograft/SMYD3-inhibitor studies in endometrial cancer cells\",\n      \"pmids\": [\"38191478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methylated residues and their structural effect not mapped\", \"Single lab, single cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A catalytic-dead knock-in established that LIG4 has a structural scaffolding role distinct from its enzymatic activity, with nuclear Lig3 able to perform ligation when LIG4 is present but inactive.\",\n      \"evidence\": \"Lig4 catalytic-site point-mutant knock-in mice crossed to nuclear Lig3-deficient strain, with lymphocyte development and lethality analysis\",\n      \"pmids\": [\"39673806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface enabling Lig3 substitution not defined\", \"Extent of scaffolding rescue across cell types unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing LIG4 catalyzes ecDNA junction ligation linked NHEJ to a cancer genome-amplification mechanism and therapy adaptation.\",\n      \"evidence\": \"Genome-wide CRISPR screen, LIG4 knockouts, ecDNA junction sequencing revealing a LIG4 signature, and drug-resistance assays across Drosophila and mammalian cells\",\n      \"pmids\": [\"41811450\", \"40027615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream events generating the circular precursors not defined\", \"Whether LIG4 ecDNA role requires the canonical XRCC4/XLF complex untested here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying PIPKIγ and lactate as enhancers of the LIG4-XRCC4 interaction revealed additional regulatory inputs that tune NHEJ-driven therapy resistance.\",\n      \"evidence\": \"Co-IP, pull-down, nuclear fractionation, XRCC4 mutagenesis/docking, and NHEJ reporter and xenograft assays in breast and ovarian cancer cells\",\n      \"pmids\": [\"40744919\", \"41462961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic detail of how interaction strengthening accelerates ligation unresolved\", \"Physiological versus pathological relevance of these inputs unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Structural and biochemical work explained how telomeres avoid LIG4-mediated fusion, by RAP1-TRF2 blocking DNA-PK recruitment of LIG4.\",\n      \"evidence\": \"Cryo-EM, biochemical reconstitution, and telomere fusion assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Whether the block is overcome under pathological telomere deprotection in vivo not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A developmental role was probed by testing whether LIG4/NHEJ is required for in vivo cellular reprogramming.\",\n      \"evidence\": \"In vivo LIG4/KU80 knockdown with PRKDC knockout and p53-knockdown rescue in a SOX2 glia-to-neuron reprogramming assay (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint and LIG4 is one of several NHEJ components tested, not isolated\", \"Direct requirement for LIG4 catalytic activity not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LIG4's many regulatory inputs (methylation, transcriptional control, interaction modifiers, and telomeric exclusion) are coordinated to determine when and where ligation proceeds remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating post-translational and partner-mediated regulation\", \"Hierarchy among Wnt, SMYD3, PIPKIγ and lactate inputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 13, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 6, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"LIG4/XRCC4/XLF NHEJ ligation complex\"],\n    \"partners\": [\"XRCC4\", \"XLF\", \"SMYD3\", \"PIPKIγ\", \"LIG3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}