{"gene":"ERCC6","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1992,"finding":"ERCC6 encodes a 1493 amino acid protein containing seven consecutive domains conserved between DNA and RNA helicases, and is specifically required for preferential (transcription-coupled) nucleotide excision repair of the transcribed strand of active genes; mutation analysis showed the gene is not essential for cell viability.","method":"Molecular cloning, complementation assay in CS-B cells, mutation analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational cloning and complementation paper, replicated across multiple subsequent studies","pmids":["1339317"],"is_preprint":false},{"year":1993,"finding":"ERCC6 spans ~82–90 kb genomic region with at least 21 exons; seven helicase signature motifs are each encoded on separate exons; expression produces two mRNA species (5 and 7 kb) via alternative polyadenylation.","method":"Genomic cloning, exon mapping, Northern blot, cDNA analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic and cDNA characterization, single lab","pmids":["8382798"],"is_preprint":false},{"year":1994,"finding":"RAD26, the S. cerevisiae homolog of ERCC6/CSB, is required for transcription-coupled repair (preferential removal of UV-induced cyclobutane pyrimidine dimers from the transcribed strand of the active RBP2 gene); rad26 disruption does not cause UV sensitivity, indicating TCR is less critical for survival in yeast.","method":"Gene disruption, UV survival assay, strand-specific CPD repair assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion with direct repair assay, foundational paper replicated by multiple subsequent studies","pmids":["7957102"],"is_preprint":false},{"year":1996,"finding":"Rad26 (yeast ERCC6/CSB ortholog) is a DNA-dependent ATPase; in contrast to E. coli Mfd (weak, DNA-independent ATPase), Rad26 has strict dependence on DNA for ATPase activity.","method":"Protein purification from yeast, in vitro ATPase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified protein reconstitution with in vitro enzymatic assay, replicated by human CSB characterization","pmids":["8702468"],"is_preprint":false},{"year":1997,"finding":"Human CSB/ERCC6 is a DNA-stimulated ATPase but is NOT a helicase and does NOT dissociate stalled RNA polymerase II ternary complexes; CSB binds DNA and interacts with XPA, TFIIH, and the p34 subunit of TFIIE.","method":"Baculovirus overexpression, protein purification, in vitro ATPase assay, helicase assay, Co-IP/pulldown with XPA, TFIIH, TFIIE-p34","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted recombinant protein, multiple in vitro enzymatic and binding assays, negative results explicitly confirmed","pmids":["8999876"],"is_preprint":false},{"year":1997,"finding":"CSB/ERCC6 interacts with RNA polymerase II engaged in ternary transcription complexes (containing DNA and nascent RNA); this interaction requires hydrolysis of the ATP β-γ phosphoanhydride bond by CSB; CSA does not directly bind Pol II.","method":"Biochemical pulldown using oligo(dC)-tailed DNA template, ATPase mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with ternary complex, ATPase mutant validation, single lab","pmids":["9372911"],"is_preprint":false},{"year":1998,"finding":"RAD26 is required for transcription in yeast cell extracts when nucleotide excision repair is active; in the presence of NER, TFIIH is preferentially mobilized for repair, inhibiting transcription, and RAD26 is required for this inhibition.","method":"Cell-free transcription and NER assay with yeast extracts, complementation with purified holo-TFIIH","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cell extract system with genetic deletion controls, single lab","pmids":["9566886"],"is_preprint":false},{"year":1999,"finding":"In rad26 mutant yeast cells, loss of TCR is not due to a transcription deficiency but to failure to overcome the nucleotide excision repair block caused by RNA polymerase II stalled at DNA damage sites; repair of transcribed sequences between nucleosomal cores is less efficient in rad26 mutants, pointing to a repair impediment from trapped RNA polymerase.","method":"Single-nucleotide resolution CPD repair mapping in vivo, transcription analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — high-resolution in vivo repair mapping with genetic deletion, single lab","pmids":["9880486"],"is_preprint":false},{"year":2000,"finding":"Deletion of SPT4 (encoding a transcription elongation factor) suppresses the rad26 TCR defect, activating Rad26-independent TCR; this indicates Rad26 functions as an elongation factor rendering transcription TCR-competent, and its requirement is modulated by Spt4.","method":"Genome-wide mutagenesis, UV survival, strand-specific repair assay in spt4 rad26 double mutants","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple orthogonal assays, replicated by subsequent studies","pmids":["11101522"],"is_preprint":false},{"year":2001,"finding":"RAD26 is required for transcription elongation by RNA polymerase II in vivo; cells lacking RAD26 show reduced transcription of galactose-inducible genes under conditions requiring rapid mRNA synthesis, with considerable growth reduction; this implicates CSB in transcription elongation and suggests impaired elongation underlies developmental defects in Cockayne syndrome.","method":"In vivo transcription assay (galactose-inducible gene expression), growth assay in S. cerevisiae","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function with defined transcriptional phenotype, single lab","pmids":["11713297"],"is_preprint":false},{"year":2002,"finding":"Rad26 forms a complex with Def1 in chromatin; Def1 is required for ubiquitination and proteolysis of RNA polymerase II (RNAPII) in response to DNA damage; Rad26-Def1 complex coordinates TCR-mediated DNA repair with RNAPII degradation when lesions cannot be rapidly removed.","method":"Co-IP, chromatin fractionation, genetic epistasis, RNAPII ubiquitination and degradation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and chromatin fractionation with functional genetic epistasis, published in high-impact journal","pmids":["11859374"],"is_preprint":false},{"year":2002,"finding":"RAD26 promotes survival of MMS-treated yeast cells independently of nucleotide excision repair and base excision repair; RAD26 facilitates transcription by RNA polymerase II through MMS-damaged (alkylated) bases, representing a distinct function from its TCR role.","method":"MMS sensitivity assay, synergistic mutant analysis (rad26Δ mag1Δ rad14Δ), galactose-inducible gene transcription assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with transcription readout, single lab","pmids":["12024048"],"is_preprint":false},{"year":2009,"finding":"The C-terminal repeat (CTR) domain of Spt5, phosphorylated by Bur kinase, suppresses Rad26-independent TCR by serving as a platform for assembly of a multi-protein suppressor complex associated with Pol II; Spt4 indirectly suppresses Rad26-independent TCR by stabilizing Spt5-Pol II interaction.","method":"Genetic epistasis (spt4Δ, spt5 CTR deletion, bur kinase mutants), in vivo TCR assay, Co-IP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple mutant combinations, single lab","pmids":["20042611"],"is_preprint":false},{"year":2009,"finding":"Mec1 kinase directly phosphorylates Rad26 (yeast CSB ortholog) in a DNA-damage-dependent manner independently of downstream kinases Rad53, Chk1, Tel1, and Dun1; mutation of the Rad26 phosphorylation site decreases the rate of TC-NER, establishing Mec1-dependent phosphorylation as a direct activation mechanism for TC-NER.","method":"In vivo phosphorylation assay, TC-NER strand-specific repair assay in phosphorylation-site mutants, kinase mutant epistasis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation with site-directed mutagenesis and functional repair assay, single lab","pmids":["19901073"],"is_preprint":false},{"year":2012,"finding":"UVSSA protein forms a complex with USP7 and stabilizes ERCC6/CSB after UV irradiation; loss of UVSSA destabilizes ERCC6 and disrupts TCR; UVSSA restores the hypophosphorylated form of RNA polymerase II after UV irradiation.","method":"Complementation cloning, Co-IP, Western blot for ERCC6 stability, RRS (recovery of RNA synthesis) assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional complementation and protein stability assay, published in high-impact journal","pmids":["22466612"],"is_preprint":false},{"year":2019,"finding":"At normal or moderately elevated levels, Rad26 promotes error-free transcriptional bypass of UV photoproducts and constitutively evicts Spt5 from chromatin; at very high overexpression (~1/3 of RNAPII levels), Rad26 loses these functions; substantial AMP (but no other nucleotides) is misincorporated opposite UV photoproducts, but Rad26 does not affect this misincorporation.","method":"Transcription elongation assay in vivo, ChIP for Spt5 eviction, nucleotide misincorporation mapping","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo chromatin and transcriptional assays with multiple genetic conditions, single lab","pmids":["30790631"],"is_preprint":false},{"year":2020,"finding":"Rad26 and its ATPase activity are critical for TC-NER downstream of the first (+1) nucleosome in gene coding regions; TC-NER at the TSS-proximal half of the +1 nucleosome is largely Rad26-independent due to high TFIIH occupancy; downstream, the combination of low TFIIH and high Spt4/Spt5 occupancy suppresses TC-NER in Rad26-deficient cells; SPT4 deletion restores TC-NER genome-wide in rad26Δ cells.","method":"Single-nucleotide resolution UV damage mapping (CPD-seq), chromatin occupancy analysis, genetic deletion epistasis (rad26Δ, spt4Δ)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide single-nucleotide resolution repair mapping with multiple genetic conditions and ChIP data","pmids":["32690696"],"is_preprint":false},{"year":2021,"finding":"Rad26 (CSB ortholog) remodels DNA through an allosteric pathway coupling ATPase module motions to changes in RNA polymerase II and DNA; the mechanism allows CSB-assisted progression past less bulky lesions; Cockayne syndrome disease mutations can be functionally interpreted in this structural context.","method":"Cryo-EM structural modeling, molecular dynamics simulation, graph-theoretical community analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — computational structural modeling with simulation (no experimental mutagenesis validation reported in abstract), single study","pmids":["34853308"],"is_preprint":false},{"year":2021,"finding":"Rad26 and TFIIS can stimulate bypass of non-template strand (NTS) CAG slip-out-induced transcriptional arrest but NOT template strand (TS) slip-out-induced distal pausing; TS slip-out induces R-loop formation at distal pausing sites; both NTS and TS slip-outs cause Pol II backtracking at proximal sites.","method":"In vitro reconstituted yeast transcription system, R-loop mapping, Pol II backtracking assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted transcription system with purified factors, single lab","pmids":["34197619"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of Pol II-Rad26 complexes stalled at different obstacles reveal that Rad26 uses a common mechanism to recognize stalled Pol II, with additional interactions when Pol II is arrested specifically at a DNA lesion; Elf1 (ELOF1 ortholog) induces further interactions between Rad26 and lesion-arrested Pol II; Elf1 and Rad26 cooperate at the initial lesion-recognition step of TC-NER.","method":"Cryo-EM structure determination, biochemical pulldown/interaction assays, genetic complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with orthogonal biochemical and genetic validation, multiple conditions","pmids":["38194460"],"is_preprint":false},{"year":2024,"finding":"ERCC6 interacts with HNRNPM and influences the PI3K/AKT signaling pathway and alternative splicing of BAX pre-mRNA; ERCC6 knockdown increases expression of full-length BAX by reducing exon 2 skipping, promoting apoptosis; exon 2 skipping introduces a premature stop codon in the BH3 domain of BAX.","method":"CRISPR screening, shRNA knockdown, Co-IP (ERCC6-HNRNPM interaction), RNA-seq (alternative splicing), xenograft model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction, in vitro and in vivo functional assays, single lab","pmids":["40476445"],"is_preprint":false},{"year":2013,"finding":"Rad26 is required for removal of stalled RNA polymerase II from chromatin following UV irradiation; in RAD26-deleted cells, no significant reduction in RNAPII occupancy occurs at damaged active loci (RPB2, PYK1, RPL2B), and transcription of RPB2 is adversely affected during DNA damage repair.","method":"Chromatin immunoprecipitation (ChIP) for RNAPII occupancy, UV survival, RT-PCR for transcription","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with genetic deletion and functional transcription readout, single lab","pmids":["23991048"],"is_preprint":false},{"year":2016,"finding":"Sen1 (senataxin ortholog) plays a more direct role than Rad26 in TCR: unlike Rad26, Sen1 is still required for efficient TCR in cells lacking Spt4, and Sen1 is required for repair at essentially all damaged sites in the transcribed strand, whereas Rad26 is important at many but not all sites.","method":"Genetic deletion epistasis (sen1, rad26, spt4 mutants), strand-specific CPD repair assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with repair assay, single lab","pmids":["27179024"],"is_preprint":false},{"year":2021,"finding":"CSB (encoded by ERCC6) interacts with VCP (valosin-containing protein) in lens epithelial cells; let-7c-5p-mediated downregulation of ERCC6 disrupts autophagic flux by preventing autophagosomes from combining with lysosomes.","method":"Co-immunoprecipitation (CSB-VCP interaction), siRNA knockdown, Western blot, immunofluorescence (LC3B puncta), miRNA mimic transfection","journal":"Current eye research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for interaction, functional autophagy assay without reconstitution, single lab","pmids":["33703976"],"is_preprint":false},{"year":2006,"finding":"A SNP in the ERCC6 5' flanking region (C-6530>G) alters the binding pattern of nuclear proteins (shifts Sp1 binding on C allele to SP1/GATA-1/OCT-1 on G allele) and increases luciferase reporter expression from the G allele; the G allele is associated with higher ERCC6 expression in lymphocytes.","method":"EMSA, luciferase reporter assay, CHIP assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter assay with multiple functional readouts, single lab","pmids":["16754848"],"is_preprint":false},{"year":2016,"finding":"UVB-induced repression of ERCC6 in lens epithelial cells is mediated by coordinated hypermethylation of a CpG site at position -441 in the Sp1-binding region of the ERCC6 promoter and histone H3K9 deacetylation, with increased association of DNMT3b and HDAC1 at this site.","method":"Bisulfite sequencing (methylation), ChIP for H3K9 acetylation/DNMT3b/HDAC1, RT-PCR and Western blot for ERCC6 expression, apoptosis assay","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple epigenomic methods (bisulfite, ChIP, expression), single lab","pmids":["27231489"],"is_preprint":false}],"current_model":"ERCC6/CSB encodes a DNA-stimulated ATPase (SWI2/SNF2 family) that is the central transcription-repair coupling factor for transcription-coupled nucleotide excision repair (TC-NER): it is recruited to RNA polymerase II stalled at DNA lesions (binding requiring ATP hydrolysis), where it cooperates with Elf1/ELOF1 for lesion recognition, facilitates removal of stalled RNAPII and recruitment of NER factors (TFIIH, XPA), evicts the elongation factor Spt5/Spt4 to relieve TC-NER suppression, and—with its partner Def1—coordinates RNAPII ubiquitination and proteolysis when lesions cannot be quickly removed; CSB is itself stabilized by UVSSA–USP7 complex after UV damage, is directly activated by Mec1/ATR-dependent phosphorylation, and additionally promotes transcription elongation through damaged bases independently of canonical NER, with loss-of-function mutations causing Cockayne syndrome."},"narrative":{"mechanistic_narrative":"ERCC6/CSB is the central transcription-repair coupling factor for transcription-coupled nucleotide excision repair (TC-NER), the pathway that preferentially removes lesions from the transcribed strand of active genes [PMID:1339317, PMID:7957102]. It is a DNA-stimulated ATPase of the helicase-motif family that nonetheless lacks helicase activity and does not by itself dissociate stalled RNA polymerase II; rather, it binds DNA and elongating RNAPII ternary complexes in a manner that strictly requires ATP hydrolysis, and physically contacts core NER factors including XPA, TFIIH, and TFIIE-p34 [PMID:1339317, PMID:8999876, PMID:9372911]. CSB/Rad26 recognizes RNAPII arrested at lesions through a common stalling-recognition mechanism augmented by additional lesion-specific contacts, and cooperates with Elf1/ELOF1 at the initial lesion-recognition step [PMID:38194460]; its ATPase module allosterically remodels DNA and Pol II to assist progression past less bulky obstacles [PMID:34853308]. CSB function in TC-NER is gated by the elongation factor Spt5/Spt4: Spt5 (with its Bur-kinase-phosphorylated C-terminal repeat) assembles a Pol II-associated complex that suppresses Rad26-independent repair, and deletion of SPT4 restores TC-NER genome-wide in CSB-deficient cells, particularly downstream of the +1 nucleosome where TFIIH occupancy is low [PMID:11101522, PMID:20042611, PMID:32690696]. When lesions cannot be rapidly removed, CSB/Rad26 partners with Def1 in chromatin to coordinate ubiquitination and proteolysis of stalled RNAPII and its eviction from damaged loci [PMID:11859374, PMID:23991048]. CSB activity is regulated post-translationally—directly phosphorylated by the Mec1/ATR checkpoint kinase to promote TC-NER [PMID:19901073] and stabilized after UV damage by the UVSSA–USP7 complex [PMID:22466612]. Beyond canonical NER, CSB promotes error-free transcriptional bypass of UV photoproducts and alkylated bases and constitutively evicts Spt5 from chromatin, defining a repair-independent elongation function [PMID:12024048, PMID:30790631]. Loss-of-function mutations in ERCC6 cause Cockayne syndrome, a connection interpretable in the context of its DNA-remodeling structural mechanism [PMID:34853308].","teleology":[{"year":1992,"claim":"Established the gene's identity and core biological assignment—a helicase-motif protein specifically required for transcription-coupled, not global, nucleotide excision repair.","evidence":"Molecular cloning and complementation of CS-B cells with mutation analysis","pmids":["1339317"],"confidence":"High","gaps":["Did not establish biochemical activity of the protein","Helicase motifs implied but enzymatic function untested"]},{"year":1994,"claim":"Demonstrated functional conservation by showing the yeast ortholog RAD26 carries out strand-specific TCR, enabling genetic dissection in a tractable system.","evidence":"Gene disruption and strand-specific CPD repair assay in S. cerevisiae","pmids":["7957102"],"confidence":"High","gaps":["Mechanism of strand selectivity unresolved","No biochemical activity defined"]},{"year":1997,"claim":"Defined the protein as a DNA-stimulated ATPase that is not a helicase and does not displace Pol II, and showed ATP-hydrolysis-dependent engagement of RNAPII ternary complexes plus contacts with core NER factors.","evidence":"Recombinant protein ATPase/helicase assays, ternary-complex pulldowns with ATPase mutants, Co-IP with XPA/TFIIH/TFIIE-p34 (building on yeast Rad26 ATPase work)","pmids":["8702468","8999876","9372911"],"confidence":"High","gaps":["How ATPase activity translates into repair coupling not defined","Structural basis of Pol II engagement unknown at this stage"]},{"year":2001,"claim":"Reframed CSB as a transcription elongation factor whose absence impairs RNAPII elongation in vivo, linking the elongation defect to Cockayne syndrome developmental phenotypes.","evidence":"In vivo galactose-inducible transcription and growth assays in rad26 yeast (with prior cell-extract transcription/TFIIH-mobilization data)","pmids":["11713297","9566886","9880486"],"confidence":"Medium","gaps":["Direct elongation mechanism not biochemically reconstituted","Relationship between elongation role and TCR role unresolved"]},{"year":2002,"claim":"Identified the Def1 partnership coupling TCR to RNAPII degradation, explaining how persistently stalled polymerases are cleared when repair cannot proceed.","evidence":"Co-IP, chromatin fractionation, genetic epistasis, RNAPII ubiquitination/degradation assays","pmids":["11859374"],"confidence":"High","gaps":["Ubiquitin ligase machinery details not fully defined","Trigger choosing repair versus degradation unknown"]},{"year":2002,"claim":"Distinguished a repair-independent function: CSB/Rad26 promotes transcription through alkylated bases separately from NER/BER, broadening its role beyond lesion excision.","evidence":"MMS sensitivity and synergistic mutant analysis with transcription readout in yeast","pmids":["12024048"],"confidence":"Medium","gaps":["Biochemical basis of damaged-base bypass unresolved","Generality across lesion types untested"]},{"year":2009,"claim":"Revealed CSB activity is post-translationally activated by the apical checkpoint kinase Mec1/ATR, connecting DNA-damage signaling directly to TC-NER kinetics.","evidence":"In vivo phosphorylation, phosphosite mutant TC-NER assay, kinase mutant epistasis","pmids":["19901073"],"confidence":"Medium","gaps":["Structural/functional consequence of phosphorylation undefined","Single lab; human CSB phosphoregulation not directly demonstrated here"]},{"year":2009,"claim":"Mapped the Spt5/Spt4 suppression mechanism that gates Rad26-independent repair, identifying the Bur-phosphorylated Spt5 CTR as a Pol II-associated suppressor platform.","evidence":"Genetic epistasis with spt4/spt5-CTR/bur mutants, in vivo TCR assays, Co-IP (with prior spt4 suppressor genetics)","pmids":["20042611","11101522"],"confidence":"Medium","gaps":["Direct competition between CSB and the suppressor complex not biochemically resolved"]},{"year":2012,"claim":"Identified UVSSA-USP7 as the complex stabilizing CSB after UV, defining how CSB protein levels and Pol II phosphostate are maintained during repair.","evidence":"Complementation cloning, Co-IP, CSB stability Westerns, recovery-of-RNA-synthesis assay in human cells","pmids":["22466612"],"confidence":"High","gaps":["Mechanism by which USP7 deubiquitinates CSB versus Pol II not fully separated"]},{"year":2016,"claim":"Refined the TCR hierarchy by showing senataxin/Sen1 acts more universally than Rad26, indicating CSB covers a major but incomplete subset of transcribed-strand lesions.","evidence":"Genetic deletion epistasis (sen1/rad26/spt4) with strand-specific CPD repair (with parallel ChIP showing CSB-dependent Pol II removal)","pmids":["27179024","23991048"],"confidence":"Medium","gaps":["Functional interplay between Sen1 and Rad26 at shared sites unresolved"]},{"year":2020,"claim":"Resolved where in genes CSB matters: its ATPase is critical for TC-NER downstream of the +1 nucleosome where TFIIH is low and Spt4/Spt5 is high, with SPT4 loss rescuing repair genome-wide.","evidence":"Single-nucleotide CPD-seq, chromatin occupancy analysis, rad26/spt4 epistasis","pmids":["32690696"],"confidence":"High","gaps":["Mechanistic link between chromatin context and CSB requirement not fully defined"]},{"year":2021,"claim":"Provided a structural/dynamic model in which the CSB ATPase module allosterically remodels DNA and Pol II, offering a framework to interpret Cockayne syndrome mutations.","evidence":"Cryo-EM modeling, molecular dynamics, community analysis","pmids":["34853308"],"confidence":"Medium","gaps":["No experimental mutagenesis validation reported","Predicted allosteric pathway not biochemically tested"]},{"year":2024,"claim":"Established the lesion-recognition step structurally, showing CSB/Rad26 uses a common Pol II-stalling recognition mode with lesion-specific contacts and cooperates with Elf1/ELOF1.","evidence":"Cryo-EM of Pol II-Rad26 complexes with biochemical and genetic validation","pmids":["38194460"],"confidence":"High","gaps":["Subsequent handoff to NER incision machinery not structurally resolved","Human ELOF1-CSB complex not directly determined here"]},{"year":2024,"claim":"Uncovered a non-canonical role in RNA processing whereby ERCC6-HNRNPM modulates BAX splicing and apoptosis, implicating CSB in PI3K/AKT signaling and cell survival.","evidence":"CRISPR screen, shRNA knockdown, Co-IP, RNA-seq splicing analysis, xenograft","pmids":["40476445"],"confidence":"Medium","gaps":["Directness of splicing regulation versus indirect effect unresolved","Relationship to repair/elongation functions unknown"]},{"year":null,"claim":"How CSB hands off the lesion-arrested polymerase to the downstream NER incision machinery, and how its repair, elongation, and RNA-processing functions are coordinated in human cells, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the CSB-to-TFIIH/XPA handoff","Integration of repair-independent functions with TC-NER undefined","Human in vivo phosphoregulation and Def1-equivalent coupling not directly demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,4,5,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,21]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10,21,16]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2,16,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,11,15]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[20]}],"complexes":["Rad26-Def1 complex","RNA polymerase II elongation complex"],"partners":["XPA","TFIIH","TFIIE (P34/GTF2E2)","RNA POLYMERASE II","DEF1","ELOF1/ELF1","UVSSA","HNRNPM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03468","full_name":"DNA excision repair protein ERCC-6","aliases":["ATP-dependent helicase ERCC6","Cockayne syndrome protein CSB"],"length_aa":1493,"mass_kda":168.4,"function":"Essential factor involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesions are rapidly removed from the transcribed strand of active genes (PubMed:16246722, PubMed:20541997, PubMed:22483866, PubMed:26620705, PubMed:32355176, PubMed:34526721, PubMed:38316879, PubMed:38600235, PubMed:38600236). Plays a central role in the initiation of the TC-NER process: specifically recognizes and binds RNA polymerase II stalled at a lesion, and mediates recruitment of ERCC8/CSA, initiating DNA damage excision by TFIIH recruitment (PubMed:32355176, PubMed:34526721, PubMed:38600235, PubMed:38600236). Upon DNA-binding, it locally modifies DNA conformation by wrapping the DNA around itself, thereby modifying the interface between stalled RNA polymerase II and DNA (PubMed:15548521). Acts as a chromatin remodeler at DSBs; DNA-dependent ATPase-dependent activity is essential for this function (PubMed:16246722, PubMed:9565609). Plays an important role in regulating the choice of the DNA double-strand breaks (DSBs) repair pathway and G2/M checkpoint activation; DNA-dependent ATPase activity is essential for this function (PubMed:25820262). Regulates the DNA repair pathway choice by inhibiting non-homologous end joining (NHEJ), thereby promoting the homologous recombination (HR)-mediated repair of DSBs during the S/G2 phases of the cell cycle (PubMed:25820262). Mediates the activation of the ATM- and CHEK2-dependent DNA damage responses thus preventing premature entry of cells into mitosis following the induction of DNA DSBs (PubMed:25820262). Remodels chromatin by evicting histones from chromatin flanking DSBs, limiting RIF1 accumulation at DSBs thereby promoting BRCA1-mediated HR (PubMed:29203878). Required for stable recruitment of ELOA and CUL5 to DNA damage sites (PubMed:28292928). Also involved in UV-induced translocation of ERCC8 to the nuclear matrix (PubMed:26620705). Essential for neuronal differentiation and neuritogenesis; regulates transcription and chromatin remodeling activities required during neurogenesis (PubMed:24874740)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q03468/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERCC6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ERCC6","total_profiled":1310},"omim":[{"mim_id":"619818","title":"ELONGATION FACTOR 1; ELOF1","url":"https://www.omim.org/entry/619818"},{"mim_id":"616946","title":"PREMATURE OVARIAN FAILURE 11; POF11","url":"https://www.omim.org/entry/616946"},{"mim_id":"615715","title":"BONE MARROW FAILURE SYNDROME 2; 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science","url":"https://pubmed.ncbi.nlm.nih.gov/28707579","citation_count":5,"is_preprint":false},{"pmid":"34197619","id":"PMC_34197619","title":"Strand-specific effect of Rad26 and TFIIS in rescuing transcriptional arrest by CAG trinucleotide repeat slip-outs.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34197619","citation_count":5,"is_preprint":false},{"pmid":"35975393","id":"PMC_35975393","title":"A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.","date":"2022","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35975393","citation_count":5,"is_preprint":false},{"pmid":"17644494","id":"PMC_17644494","title":"Tfb5 is partially dispensable for Rad26 mediated transcription coupled nucleotide excision repair in yeast.","date":"2007","source":"DNA 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/26749132","citation_count":4,"is_preprint":false},{"pmid":"23599700","id":"PMC_23599700","title":"Identification of Two Novel ERCC6 Mutations in Old Order Amish with Cockayne Syndrome.","date":"2012","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/23599700","citation_count":4,"is_preprint":false},{"pmid":"34005834","id":"PMC_34005834","title":"Genetic pleiotropy of ERCC6 loss-of-function and deleterious missense variants links retinal dystrophy, arrhythmia, and immunodeficiency in diverse ancestries.","date":"2021","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/34005834","citation_count":3,"is_preprint":false},{"pmid":"38152055","id":"PMC_38152055","title":"CircMAP3K4 Suppresses H2O2-Induced Human Lens Epithelial Cell Injury by miR-630/ERCC6 Axis in Age-Related Cataract.","date":"2023","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/38152055","citation_count":3,"is_preprint":false},{"pmid":"10437118","id":"PMC_10437118","title":"Neuronal ERCC6 mRNA expression in rat brain induced by a transient focal cerebral ischemia.","date":"1999","source":"Zhongguo yao li xue bao = Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/10437118","citation_count":3,"is_preprint":false},{"pmid":"35668072","id":"PMC_35668072","title":"Whole-exome sequencing revealed a novel ERCC6 variant in a Vietnamese patient with Cockayne syndrome.","date":"2022","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/35668072","citation_count":3,"is_preprint":false},{"pmid":"34271225","id":"PMC_34271225","title":"Generation of an induced pluripotent stem cell line (IUFi001) from a Cockayne syndrome patient carrying a mutation in the ERCC6 gene.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34271225","citation_count":3,"is_preprint":false},{"pmid":"35738899","id":"PMC_35738899","title":"Genomic analysis of Rad26 and Rad1-Rad10 reveals differences in their dependence on Mediator and RNA polymerase II.","date":"2022","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/35738899","citation_count":2,"is_preprint":false},{"pmid":"36802454","id":"PMC_36802454","title":"ERCC6 plays a promoting role in the progression of non-small cell lung cancer.","date":"2023","source":"Biochemistry and cell biology = Biochimie et biologie cellulaire","url":"https://pubmed.ncbi.nlm.nih.gov/36802454","citation_count":2,"is_preprint":false},{"pmid":"27791261","id":"PMC_27791261","title":"Meta-analysis reveals no significant association between ERCC6 polymorphisms and bladder cancer risk.","date":"2017","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/27791261","citation_count":1,"is_preprint":false},{"pmid":"39473441","id":"PMC_39473441","title":"Preimplantation genetic testing for Cockayne syndrome with a novel ERCC6 variant in a Chinese family.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39473441","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47655,"output_tokens":5890,"usd":0.115657,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14598,"output_tokens":4538,"usd":0.09322,"stage2_stop_reason":"end_turn"},"total_usd":0.208877,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"ERCC6 encodes a 1493 amino acid protein containing seven consecutive domains conserved between DNA and RNA helicases, and is specifically required for preferential (transcription-coupled) nucleotide excision repair of the transcribed strand of active genes; mutation analysis showed the gene is not essential for cell viability.\",\n      \"method\": \"Molecular cloning, complementation assay in CS-B cells, mutation analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — foundational cloning and complementation paper, replicated across multiple subsequent studies\",\n      \"pmids\": [\"1339317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"ERCC6 spans ~82–90 kb genomic region with at least 21 exons; seven helicase signature motifs are each encoded on separate exons; expression produces two mRNA species (5 and 7 kb) via alternative polyadenylation.\",\n      \"method\": \"Genomic cloning, exon mapping, Northern blot, cDNA analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic and cDNA characterization, single lab\",\n      \"pmids\": [\"8382798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"RAD26, the S. cerevisiae homolog of ERCC6/CSB, is required for transcription-coupled repair (preferential removal of UV-induced cyclobutane pyrimidine dimers from the transcribed strand of the active RBP2 gene); rad26 disruption does not cause UV sensitivity, indicating TCR is less critical for survival in yeast.\",\n      \"method\": \"Gene disruption, UV survival assay, strand-specific CPD repair assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion with direct repair assay, foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"7957102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Rad26 (yeast ERCC6/CSB ortholog) is a DNA-dependent ATPase; in contrast to E. coli Mfd (weak, DNA-independent ATPase), Rad26 has strict dependence on DNA for ATPase activity.\",\n      \"method\": \"Protein purification from yeast, in vitro ATPase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified protein reconstitution with in vitro enzymatic assay, replicated by human CSB characterization\",\n      \"pmids\": [\"8702468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human CSB/ERCC6 is a DNA-stimulated ATPase but is NOT a helicase and does NOT dissociate stalled RNA polymerase II ternary complexes; CSB binds DNA and interacts with XPA, TFIIH, and the p34 subunit of TFIIE.\",\n      \"method\": \"Baculovirus overexpression, protein purification, in vitro ATPase assay, helicase assay, Co-IP/pulldown with XPA, TFIIH, TFIIE-p34\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted recombinant protein, multiple in vitro enzymatic and binding assays, negative results explicitly confirmed\",\n      \"pmids\": [\"8999876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CSB/ERCC6 interacts with RNA polymerase II engaged in ternary transcription complexes (containing DNA and nascent RNA); this interaction requires hydrolysis of the ATP β-γ phosphoanhydride bond by CSB; CSA does not directly bind Pol II.\",\n      \"method\": \"Biochemical pulldown using oligo(dC)-tailed DNA template, ATPase mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with ternary complex, ATPase mutant validation, single lab\",\n      \"pmids\": [\"9372911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RAD26 is required for transcription in yeast cell extracts when nucleotide excision repair is active; in the presence of NER, TFIIH is preferentially mobilized for repair, inhibiting transcription, and RAD26 is required for this inhibition.\",\n      \"method\": \"Cell-free transcription and NER assay with yeast extracts, complementation with purified holo-TFIIH\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cell extract system with genetic deletion controls, single lab\",\n      \"pmids\": [\"9566886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In rad26 mutant yeast cells, loss of TCR is not due to a transcription deficiency but to failure to overcome the nucleotide excision repair block caused by RNA polymerase II stalled at DNA damage sites; repair of transcribed sequences between nucleosomal cores is less efficient in rad26 mutants, pointing to a repair impediment from trapped RNA polymerase.\",\n      \"method\": \"Single-nucleotide resolution CPD repair mapping in vivo, transcription analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — high-resolution in vivo repair mapping with genetic deletion, single lab\",\n      \"pmids\": [\"9880486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Deletion of SPT4 (encoding a transcription elongation factor) suppresses the rad26 TCR defect, activating Rad26-independent TCR; this indicates Rad26 functions as an elongation factor rendering transcription TCR-competent, and its requirement is modulated by Spt4.\",\n      \"method\": \"Genome-wide mutagenesis, UV survival, strand-specific repair assay in spt4 rad26 double mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple orthogonal assays, replicated by subsequent studies\",\n      \"pmids\": [\"11101522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RAD26 is required for transcription elongation by RNA polymerase II in vivo; cells lacking RAD26 show reduced transcription of galactose-inducible genes under conditions requiring rapid mRNA synthesis, with considerable growth reduction; this implicates CSB in transcription elongation and suggests impaired elongation underlies developmental defects in Cockayne syndrome.\",\n      \"method\": \"In vivo transcription assay (galactose-inducible gene expression), growth assay in S. cerevisiae\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"11713297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rad26 forms a complex with Def1 in chromatin; Def1 is required for ubiquitination and proteolysis of RNA polymerase II (RNAPII) in response to DNA damage; Rad26-Def1 complex coordinates TCR-mediated DNA repair with RNAPII degradation when lesions cannot be rapidly removed.\",\n      \"method\": \"Co-IP, chromatin fractionation, genetic epistasis, RNAPII ubiquitination and degradation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and chromatin fractionation with functional genetic epistasis, published in high-impact journal\",\n      \"pmids\": [\"11859374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RAD26 promotes survival of MMS-treated yeast cells independently of nucleotide excision repair and base excision repair; RAD26 facilitates transcription by RNA polymerase II through MMS-damaged (alkylated) bases, representing a distinct function from its TCR role.\",\n      \"method\": \"MMS sensitivity assay, synergistic mutant analysis (rad26Δ mag1Δ rad14Δ), galactose-inducible gene transcription assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with transcription readout, single lab\",\n      \"pmids\": [\"12024048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal repeat (CTR) domain of Spt5, phosphorylated by Bur kinase, suppresses Rad26-independent TCR by serving as a platform for assembly of a multi-protein suppressor complex associated with Pol II; Spt4 indirectly suppresses Rad26-independent TCR by stabilizing Spt5-Pol II interaction.\",\n      \"method\": \"Genetic epistasis (spt4Δ, spt5 CTR deletion, bur kinase mutants), in vivo TCR assay, Co-IP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple mutant combinations, single lab\",\n      \"pmids\": [\"20042611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mec1 kinase directly phosphorylates Rad26 (yeast CSB ortholog) in a DNA-damage-dependent manner independently of downstream kinases Rad53, Chk1, Tel1, and Dun1; mutation of the Rad26 phosphorylation site decreases the rate of TC-NER, establishing Mec1-dependent phosphorylation as a direct activation mechanism for TC-NER.\",\n      \"method\": \"In vivo phosphorylation assay, TC-NER strand-specific repair assay in phosphorylation-site mutants, kinase mutant epistasis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation with site-directed mutagenesis and functional repair assay, single lab\",\n      \"pmids\": [\"19901073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UVSSA protein forms a complex with USP7 and stabilizes ERCC6/CSB after UV irradiation; loss of UVSSA destabilizes ERCC6 and disrupts TCR; UVSSA restores the hypophosphorylated form of RNA polymerase II after UV irradiation.\",\n      \"method\": \"Complementation cloning, Co-IP, Western blot for ERCC6 stability, RRS (recovery of RNA synthesis) assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional complementation and protein stability assay, published in high-impact journal\",\n      \"pmids\": [\"22466612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"At normal or moderately elevated levels, Rad26 promotes error-free transcriptional bypass of UV photoproducts and constitutively evicts Spt5 from chromatin; at very high overexpression (~1/3 of RNAPII levels), Rad26 loses these functions; substantial AMP (but no other nucleotides) is misincorporated opposite UV photoproducts, but Rad26 does not affect this misincorporation.\",\n      \"method\": \"Transcription elongation assay in vivo, ChIP for Spt5 eviction, nucleotide misincorporation mapping\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo chromatin and transcriptional assays with multiple genetic conditions, single lab\",\n      \"pmids\": [\"30790631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rad26 and its ATPase activity are critical for TC-NER downstream of the first (+1) nucleosome in gene coding regions; TC-NER at the TSS-proximal half of the +1 nucleosome is largely Rad26-independent due to high TFIIH occupancy; downstream, the combination of low TFIIH and high Spt4/Spt5 occupancy suppresses TC-NER in Rad26-deficient cells; SPT4 deletion restores TC-NER genome-wide in rad26Δ cells.\",\n      \"method\": \"Single-nucleotide resolution UV damage mapping (CPD-seq), chromatin occupancy analysis, genetic deletion epistasis (rad26Δ, spt4Δ)\",\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 single-nucleotide resolution repair mapping with multiple genetic conditions and ChIP data\",\n      \"pmids\": [\"32690696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rad26 (CSB ortholog) remodels DNA through an allosteric pathway coupling ATPase module motions to changes in RNA polymerase II and DNA; the mechanism allows CSB-assisted progression past less bulky lesions; Cockayne syndrome disease mutations can be functionally interpreted in this structural context.\",\n      \"method\": \"Cryo-EM structural modeling, molecular dynamics simulation, graph-theoretical community analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — computational structural modeling with simulation (no experimental mutagenesis validation reported in abstract), single study\",\n      \"pmids\": [\"34853308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rad26 and TFIIS can stimulate bypass of non-template strand (NTS) CAG slip-out-induced transcriptional arrest but NOT template strand (TS) slip-out-induced distal pausing; TS slip-out induces R-loop formation at distal pausing sites; both NTS and TS slip-outs cause Pol II backtracking at proximal sites.\",\n      \"method\": \"In vitro reconstituted yeast transcription system, R-loop mapping, Pol II backtracking assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted transcription system with purified factors, single lab\",\n      \"pmids\": [\"34197619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of Pol II-Rad26 complexes stalled at different obstacles reveal that Rad26 uses a common mechanism to recognize stalled Pol II, with additional interactions when Pol II is arrested specifically at a DNA lesion; Elf1 (ELOF1 ortholog) induces further interactions between Rad26 and lesion-arrested Pol II; Elf1 and Rad26 cooperate at the initial lesion-recognition step of TC-NER.\",\n      \"method\": \"Cryo-EM structure determination, biochemical pulldown/interaction assays, genetic complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with orthogonal biochemical and genetic validation, multiple conditions\",\n      \"pmids\": [\"38194460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ERCC6 interacts with HNRNPM and influences the PI3K/AKT signaling pathway and alternative splicing of BAX pre-mRNA; ERCC6 knockdown increases expression of full-length BAX by reducing exon 2 skipping, promoting apoptosis; exon 2 skipping introduces a premature stop codon in the BH3 domain of BAX.\",\n      \"method\": \"CRISPR screening, shRNA knockdown, Co-IP (ERCC6-HNRNPM interaction), RNA-seq (alternative splicing), xenograft model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction, in vitro and in vivo functional assays, single lab\",\n      \"pmids\": [\"40476445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rad26 is required for removal of stalled RNA polymerase II from chromatin following UV irradiation; in RAD26-deleted cells, no significant reduction in RNAPII occupancy occurs at damaged active loci (RPB2, PYK1, RPL2B), and transcription of RPB2 is adversely affected during DNA damage repair.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for RNAPII occupancy, UV survival, RT-PCR for transcription\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with genetic deletion and functional transcription readout, single lab\",\n      \"pmids\": [\"23991048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sen1 (senataxin ortholog) plays a more direct role than Rad26 in TCR: unlike Rad26, Sen1 is still required for efficient TCR in cells lacking Spt4, and Sen1 is required for repair at essentially all damaged sites in the transcribed strand, whereas Rad26 is important at many but not all sites.\",\n      \"method\": \"Genetic deletion epistasis (sen1, rad26, spt4 mutants), strand-specific CPD repair assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with repair assay, single lab\",\n      \"pmids\": [\"27179024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CSB (encoded by ERCC6) interacts with VCP (valosin-containing protein) in lens epithelial cells; let-7c-5p-mediated downregulation of ERCC6 disrupts autophagic flux by preventing autophagosomes from combining with lysosomes.\",\n      \"method\": \"Co-immunoprecipitation (CSB-VCP interaction), siRNA knockdown, Western blot, immunofluorescence (LC3B puncta), miRNA mimic transfection\",\n      \"journal\": \"Current eye research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for interaction, functional autophagy assay without reconstitution, single lab\",\n      \"pmids\": [\"33703976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A SNP in the ERCC6 5' flanking region (C-6530>G) alters the binding pattern of nuclear proteins (shifts Sp1 binding on C allele to SP1/GATA-1/OCT-1 on G allele) and increases luciferase reporter expression from the G allele; the G allele is associated with higher ERCC6 expression in lymphocytes.\",\n      \"method\": \"EMSA, luciferase reporter assay, CHIP assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter assay with multiple functional readouts, single lab\",\n      \"pmids\": [\"16754848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UVB-induced repression of ERCC6 in lens epithelial cells is mediated by coordinated hypermethylation of a CpG site at position -441 in the Sp1-binding region of the ERCC6 promoter and histone H3K9 deacetylation, with increased association of DNMT3b and HDAC1 at this site.\",\n      \"method\": \"Bisulfite sequencing (methylation), ChIP for H3K9 acetylation/DNMT3b/HDAC1, RT-PCR and Western blot for ERCC6 expression, apoptosis assay\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple epigenomic methods (bisulfite, ChIP, expression), single lab\",\n      \"pmids\": [\"27231489\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERCC6/CSB encodes a DNA-stimulated ATPase (SWI2/SNF2 family) that is the central transcription-repair coupling factor for transcription-coupled nucleotide excision repair (TC-NER): it is recruited to RNA polymerase II stalled at DNA lesions (binding requiring ATP hydrolysis), where it cooperates with Elf1/ELOF1 for lesion recognition, facilitates removal of stalled RNAPII and recruitment of NER factors (TFIIH, XPA), evicts the elongation factor Spt5/Spt4 to relieve TC-NER suppression, and—with its partner Def1—coordinates RNAPII ubiquitination and proteolysis when lesions cannot be quickly removed; CSB is itself stabilized by UVSSA–USP7 complex after UV damage, is directly activated by Mec1/ATR-dependent phosphorylation, and additionally promotes transcription elongation through damaged bases independently of canonical NER, with loss-of-function mutations causing Cockayne syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERCC6/CSB is the central transcription-repair coupling factor for transcription-coupled nucleotide excision repair (TC-NER), the pathway that preferentially removes lesions from the transcribed strand of active genes [#0, #2]. It is a DNA-stimulated ATPase of the helicase-motif family that nonetheless lacks helicase activity and does not by itself dissociate stalled RNA polymerase II; rather, it binds DNA and elongating RNAPII ternary complexes in a manner that strictly requires ATP hydrolysis, and physically contacts core NER factors including XPA, TFIIH, and TFIIE-p34 [#0, #4, #5]. CSB/Rad26 recognizes RNAPII arrested at lesions through a common stalling-recognition mechanism augmented by additional lesion-specific contacts, and cooperates with Elf1/ELOF1 at the initial lesion-recognition step [#19]; its ATPase module allosterically remodels DNA and Pol II to assist progression past less bulky obstacles [#17]. CSB function in TC-NER is gated by the elongation factor Spt5/Spt4: Spt5 (with its Bur-kinase-phosphorylated C-terminal repeat) assembles a Pol II-associated complex that suppresses Rad26-independent repair, and deletion of SPT4 restores TC-NER genome-wide in CSB-deficient cells, particularly downstream of the +1 nucleosome where TFIIH occupancy is low [#8, #12, #16]. When lesions cannot be rapidly removed, CSB/Rad26 partners with Def1 in chromatin to coordinate ubiquitination and proteolysis of stalled RNAPII and its eviction from damaged loci [#10, #21]. CSB activity is regulated post-translationally—directly phosphorylated by the Mec1/ATR checkpoint kinase to promote TC-NER [#13] and stabilized after UV damage by the UVSSA–USP7 complex [#14]. Beyond canonical NER, CSB promotes error-free transcriptional bypass of UV photoproducts and alkylated bases and constitutively evicts Spt5 from chromatin, defining a repair-independent elongation function [#11, #15]. Loss-of-function mutations in ERCC6 cause Cockayne syndrome, a connection interpretable in the context of its DNA-remodeling structural mechanism [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the gene's identity and core biological assignment—a helicase-motif protein specifically required for transcription-coupled, not global, nucleotide excision repair.\",\n      \"evidence\": \"Molecular cloning and complementation of CS-B cells with mutation analysis\",\n      \"pmids\": [\"1339317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish biochemical activity of the protein\", \"Helicase motifs implied but enzymatic function untested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrated functional conservation by showing the yeast ortholog RAD26 carries out strand-specific TCR, enabling genetic dissection in a tractable system.\",\n      \"evidence\": \"Gene disruption and strand-specific CPD repair assay in S. cerevisiae\",\n      \"pmids\": [\"7957102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of strand selectivity unresolved\", \"No biochemical activity defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the protein as a DNA-stimulated ATPase that is not a helicase and does not displace Pol II, and showed ATP-hydrolysis-dependent engagement of RNAPII ternary complexes plus contacts with core NER factors.\",\n      \"evidence\": \"Recombinant protein ATPase/helicase assays, ternary-complex pulldowns with ATPase mutants, Co-IP with XPA/TFIIH/TFIIE-p34 (building on yeast Rad26 ATPase work)\",\n      \"pmids\": [\"8702468\", \"8999876\", \"9372911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATPase activity translates into repair coupling not defined\", \"Structural basis of Pol II engagement unknown at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reframed CSB as a transcription elongation factor whose absence impairs RNAPII elongation in vivo, linking the elongation defect to Cockayne syndrome developmental phenotypes.\",\n      \"evidence\": \"In vivo galactose-inducible transcription and growth assays in rad26 yeast (with prior cell-extract transcription/TFIIH-mobilization data)\",\n      \"pmids\": [\"11713297\", \"9566886\", \"9880486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct elongation mechanism not biochemically reconstituted\", \"Relationship between elongation role and TCR role unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identified the Def1 partnership coupling TCR to RNAPII degradation, explaining how persistently stalled polymerases are cleared when repair cannot proceed.\",\n      \"evidence\": \"Co-IP, chromatin fractionation, genetic epistasis, RNAPII ubiquitination/degradation assays\",\n      \"pmids\": [\"11859374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase machinery details not fully defined\", \"Trigger choosing repair versus degradation unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Distinguished a repair-independent function: CSB/Rad26 promotes transcription through alkylated bases separately from NER/BER, broadening its role beyond lesion excision.\",\n      \"evidence\": \"MMS sensitivity and synergistic mutant analysis with transcription readout in yeast\",\n      \"pmids\": [\"12024048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of damaged-base bypass unresolved\", \"Generality across lesion types untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed CSB activity is post-translationally activated by the apical checkpoint kinase Mec1/ATR, connecting DNA-damage signaling directly to TC-NER kinetics.\",\n      \"evidence\": \"In vivo phosphorylation, phosphosite mutant TC-NER assay, kinase mutant epistasis\",\n      \"pmids\": [\"19901073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural/functional consequence of phosphorylation undefined\", \"Single lab; human CSB phosphoregulation not directly demonstrated here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped the Spt5/Spt4 suppression mechanism that gates Rad26-independent repair, identifying the Bur-phosphorylated Spt5 CTR as a Pol II-associated suppressor platform.\",\n      \"evidence\": \"Genetic epistasis with spt4/spt5-CTR/bur mutants, in vivo TCR assays, Co-IP (with prior spt4 suppressor genetics)\",\n      \"pmids\": [\"20042611\", \"11101522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition between CSB and the suppressor complex not biochemically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified UVSSA-USP7 as the complex stabilizing CSB after UV, defining how CSB protein levels and Pol II phosphostate are maintained during repair.\",\n      \"evidence\": \"Complementation cloning, Co-IP, CSB stability Westerns, recovery-of-RNA-synthesis assay in human cells\",\n      \"pmids\": [\"22466612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which USP7 deubiquitinates CSB versus Pol II not fully separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the TCR hierarchy by showing senataxin/Sen1 acts more universally than Rad26, indicating CSB covers a major but incomplete subset of transcribed-strand lesions.\",\n      \"evidence\": \"Genetic deletion epistasis (sen1/rad26/spt4) with strand-specific CPD repair (with parallel ChIP showing CSB-dependent Pol II removal)\",\n      \"pmids\": [\"27179024\", \"23991048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional interplay between Sen1 and Rad26 at shared sites unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved where in genes CSB matters: its ATPase is critical for TC-NER downstream of the +1 nucleosome where TFIIH is low and Spt4/Spt5 is high, with SPT4 loss rescuing repair genome-wide.\",\n      \"evidence\": \"Single-nucleotide CPD-seq, chromatin occupancy analysis, rad26/spt4 epistasis\",\n      \"pmids\": [\"32690696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between chromatin context and CSB requirement not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a structural/dynamic model in which the CSB ATPase module allosterically remodels DNA and Pol II, offering a framework to interpret Cockayne syndrome mutations.\",\n      \"evidence\": \"Cryo-EM modeling, molecular dynamics, community analysis\",\n      \"pmids\": [\"34853308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental mutagenesis validation reported\", \"Predicted allosteric pathway not biochemically tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the lesion-recognition step structurally, showing CSB/Rad26 uses a common Pol II-stalling recognition mode with lesion-specific contacts and cooperates with Elf1/ELOF1.\",\n      \"evidence\": \"Cryo-EM of Pol II-Rad26 complexes with biochemical and genetic validation\",\n      \"pmids\": [\"38194460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subsequent handoff to NER incision machinery not structurally resolved\", \"Human ELOF1-CSB complex not directly determined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a non-canonical role in RNA processing whereby ERCC6-HNRNPM modulates BAX splicing and apoptosis, implicating CSB in PI3K/AKT signaling and cell survival.\",\n      \"evidence\": \"CRISPR screen, shRNA knockdown, Co-IP, RNA-seq splicing analysis, xenograft\",\n      \"pmids\": [\"40476445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directness of splicing regulation versus indirect effect unresolved\", \"Relationship to repair/elongation functions unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CSB hands off the lesion-arrested polymerase to the downstream NER incision machinery, and how its repair, elongation, and RNA-processing functions are coordinated in human cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the CSB-to-TFIIH/XPA handoff\", \"Integration of repair-independent functions with TC-NER undefined\", \"Human in vivo phosphoregulation and Def1-equivalent coupling not directly demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 4, 5, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 21]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10, 21, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2, 16, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 11, 15]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [\"Rad26-Def1 complex\", \"RNA polymerase II elongation complex\"],\n    \"partners\": [\"XPA\", \"TFIIH\", \"TFIIE (p34/GTF2E2)\", \"RNA polymerase II\", \"DEF1\", \"ELOF1/Elf1\", \"UVSSA\", \"HNRNPM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}