Affinage

ERCC6

DNA excision repair protein ERCC-6 · UniProt Q03468

Length
1493 aa
Mass
168.4 kDa
Annotated
2026-04-28
100 papers in source corpus 38 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ERCC6/CSB is an ATP-dependent SWI2/SNF2-family chromatin remodeler that serves as a master coordinator of transcription-coupled DNA repair and transcription recovery at sites of RNA polymerase stalling. CSB is a DNA-stimulated ATPase (not a helicase) that wraps DNA in an ATP-dependent manner, physically associates with elongating RNA polymerase II through ATP hydrolysis, and is recruited to stalled polymerases at UV-induced lesions, oxidative damage (8-oxoguanine), interstrand crosslinks, and DNA-protein crosslinks to initiate transcription-coupled nucleotide excision repair and transcription-coupled base excision repair (PMID:1339317, PMID:8999876, PMID:9372911, PMID:10786832, PMID:38600235, PMID:29955842). Its chromatin association is autoinhibited by an N-terminal region and activated by ATP hydrolysis and phosphorylation (ATM on S10, CDK2 on S158, CDK on S1276), enabling functions beyond TC-NER including histone eviction at DSBs to promote HR over NHEJ, BRCA1/2-independent homologous recombination at R-loops via RAD52 recruitment, telomere maintenance in ALT cells, RNA polymerase I-dependent rRNA synthesis, and PAF1C loading onto RNAPII for post-damage transcription restart (PMID:20122405, PMID:29203878, PMID:30297739, PMID:31501894, PMID:12419226, PMID:33637760). CSB is regulated by CSA-DDB1-CUL4A E3 ligase-mediated ubiquitination and VCP/p97-dependent proteasomal degradation after repair completion, and is stabilized by the UVSSA-USP7 complex; loss-of-function mutations cause Cockayne syndrome, a multisystem disorder of defective transcription-coupled repair (PMID:16751180, PMID:22466612, PMID:26826127).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1990 High

    Cloning of ERCC6 by functional complementation of the UV-sensitive CHO mutant UV61 established that a single gene corrects a specific deficiency in cyclobutane pyrimidine dimer repair, linking ERCC6 to a distinct DNA repair pathway.

    Evidence Genomic DNA transfection and complementation cloning in CHO UV61 cells

    PMID:2172786

    Open questions at the time
    • No protein product characterized
    • Mechanism of repair deficiency unknown
    • Human disease connection not yet established
  2. 1992 High

    Full-length cloning and characterization of the ERCC6/CSB protein revealed SWI2/SNF2-family helicase motifs and demonstrated that CSB is specifically required for transcription-coupled NER — the preferential repair of lesions on the transcribed strand of active genes — establishing the molecular identity of the Cockayne syndrome group B gene.

    Evidence cDNA cloning, complementation of CS-B patient cells, domain analysis, mutation identification

    PMID:1339317

    Open questions at the time
    • Biochemical activity of the protein unknown
    • Mechanism of coupling to transcription unclear
  3. 1994 High

    Identification of RAD26 as the yeast ortholog of ERCC6 confirmed that transcription-coupled repair is an evolutionarily conserved pathway, though dispensability for UV survival in yeast suggested additional functions in mammals.

    Evidence Gene disruption and strand-specific repair assay in S. cerevisiae

    PMID:7957102

    Open questions at the time
    • Why yeast tolerates loss of TCR while human cells do not
    • Direct protein activity of Rad26 not yet measured
  4. 1997 High

    Biochemical reconstitution resolved the paradox of CSB's helicase motifs: CSB is a DNA-stimulated ATPase but not a helicase, and it physically interacts with elongating RNA polymerase II in an ATP-hydrolysis-dependent manner, establishing the mechanism of TC-NER initiation.

    Evidence Purified recombinant CSB — ATPase, helicase, and Pol II ternary complex binding assays with ATPase mutants

    PMID:8999876 PMID:9372911

    Open questions at the time
    • Whether CSB remodels chromatin directly
    • How ATP hydrolysis stabilizes the Pol II interaction structurally
  5. 2000 High

    Demonstration that CSB is required for transcription-coupled repair of 8-oxoguanine expanded CSB's substrate repertoire beyond UV-induced CPDs to oxidative base lesions, explaining why CS patients exhibit features beyond UV sensitivity.

    Evidence Strand-specific repair and mutation frequency assays in CS-B cell lines

    PMID:10786832

    Open questions at the time
    • Whether CSB recruits BER factors or only initiates TCR at oxidative lesions
    • Mechanism of Pol II stalling at 8-oxoG
  6. 2002 High

    Discovery that CSB resides in a nucleolar complex with RNA Pol I, TFIIH, and XPG and promotes rRNA synthesis revealed that CSB functions extend beyond DNA repair to active transcription by RNA polymerase I.

    Evidence Immunoprecipitation, in vitro RNA Pol I transcription, complementation in CSB-deficient cells

    PMID:12419226

    Open questions at the time
    • Whether CSB remodels rDNA chromatin directly
    • Contribution to Cockayne syndrome neurodegeneration
  7. 2004 High

    Biophysical studies established that CSB wraps DNA around itself in an ATP-dependent manner and transiently associates with the transcription elongation machinery, with UV damage prolonging this association — defining CSB as a bona fide chromatin remodeler acting at sites of transcription arrest.

    Evidence Scanning force microscopy of DNA-CSB complexes and live-cell FRAP of GFP-CSB

    PMID:15226310 PMID:15548521

    Open questions at the time
    • Nucleosome substrate remodeling not yet directly shown
    • No structural model of CSB on chromatin
  8. 2006 High

    Identification of CSB as a substrate of the CSA-containing CRL4 E3 ubiquitin ligase resolved how TC-NER is terminated: UV-induced ubiquitination and proteasomal degradation of CSB is required for post-repair transcription recovery.

    Evidence Ubiquitination assays, proteasome inhibition, CSA-deficient cells, RNA synthesis recovery

    PMID:16751180

    Open questions at the time
    • Identity of the ubiquitin chain type on CSB
    • How CSB degradation timing is controlled
  9. 2010 High

    Mapping of an N-terminal autoinhibitory domain that restricts CSB's chromatin association during normal growth, overcome by ATP hydrolysis upon UV damage, provided a regulatory mechanism ensuring CSB activation is lesion-dependent.

    Evidence Chromatin fractionation with ATPase and N-terminal deletion mutants

    PMID:20122405

    Open questions at the time
    • Structural basis of autoinhibition in human CSB
    • Whether post-translational modifications regulate autoinhibition
  10. 2012 High

    Discovery that UVSSA-USP7 stabilizes CSB protein levels explained how CSB abundance is maintained during repair and identified UVSSA mutations as the cause of UV-sensitive syndrome, distinguishing it from Cockayne syndrome.

    Evidence Complementation cloning, co-immunoprecipitation, CSB stability western blots

    PMID:22466612

    Open questions at the time
    • Precise ubiquitin editing mechanism on CSB by USP7
    • Whether UVSSA modulates CSB activity beyond stabilization
  11. 2014 High

    Characterization of a conserved 'leucine latch' motif in the CSB ortholog Rhp26 defined the structural basis of N-terminal autoinhibition of ATPase and remodeling activity, with the C-terminus serving as a counterbalance — a mechanism conserved to human CSB.

    Evidence Mutagenesis, in vitro ATPase and nucleosome remodeling, in vivo complementation in S. pombe

    PMID:25512493

    Open questions at the time
    • Direct demonstration of leucine-latch mechanism in human CSB
    • Allosteric coupling mechanism between termini and ATPase domain
  12. 2017 High

    Three contemporaneous studies expanded CSB's functions to DSB repair pathway choice and R-loop-dependent homologous recombination: ATM/CDK2-dependent phosphorylation drives CSB's chromatin remodeling at DSBs to evict histones and promote HR over NHEJ, while CSB senses R-loops and recruits RAD52 for BRCA1/2-independent HR, and NAP1L1 enhances CSB nucleosome remodeling processivity.

    Evidence Phospho-mutant analysis with histone eviction assays; in vitro DNA:RNA hybrid binding with epistasis; single-molecule FRET nucleosome remodeling

    PMID:28369616 PMID:29203878 PMID:30297739

    Open questions at the time
    • Whether CSB-RAD52 HR operates at non-telomeric loci genome-wide
    • Structural basis of CSB recognition of R-loops versus naked DNA
  13. 2018 High

    Live-cell imaging demonstrated that CSB specifically recruits XRCC1 to 8-oxoG lesions in a transcription-dependent manner, establishing CSB as a bridge between stalled Pol II and downstream BER completion at transcribed genes.

    Evidence Laser-induced 8-oxoG with fluorescent XRCC1/OGG1 recruitment kinetics in CSB-KO cells

    PMID:29955842

    Open questions at the time
    • Whether CSB physically contacts XRCC1 or acts indirectly through chromatin remodeling
    • Full BER intermediate processing at stalled Pol II sites
  14. 2019 High

    CDK-dependent phosphorylation of CSB at S1276 mediates interaction with BRCA1-BRCT domain, promoting MRN/CtIP-mediated end resection for HR at DSBs — separating CSB's resection-promoting function from its histone-eviction activity.

    Evidence Phospho-mutant co-IP, CDK inhibitor treatment, end resection assays

    PMID:31501894

    Open questions at the time
    • Whether S1276 phosphorylation and S10/S158 phosphorylation are coordinated temporally
    • Structural basis of CSB-BRCA1 BRCT interaction
  15. 2020 High

    CSB was shown to operate at telomeres in ALT cells, where it recruits RAD52 and POLD3 for break-induced replication at R-loop-containing telomeric DSBs, extending CSB's R-loop repair function to telomere maintenance.

    Evidence ChIP, live-cell imaging, epistasis with CSB/RAD52/POLD3 knockdown, S9.6 R-loop detection at telomeres

    PMID:31777915 PMID:31974116

    Open questions at the time
    • Whether CSB is required for ALT telomere maintenance in vivo (animal model)
    • Mechanism distinguishing telomeric from genomic R-loop repair
  16. 2021 High

    Discovery that CSB loads PAF1C onto RNAPII at promoter-proximal regions after DNA damage resolved how transcription restarts genome-wide after genotoxic stress — PAF1C is dispensable for repair itself but essential for elongation recovery.

    Evidence Co-IP, ChIP-seq, mass spectrometry, RNA recovery assays, PAF1C knockdown

    PMID:33637760

    Open questions at the time
    • Whether CSB-PAF1C loading is specific to UV or general across damage types
    • Structural basis of CSB-PAF1C-RNAPII assembly
  17. 2023 Medium

    CSB was placed downstream of PARP1/2 signaling at oxidatively damaged transcribed DNA, where it promotes XRCC1, HPF1 recruitment and histone PARylation for single-strand break repair — a function bypassed when transcription is inhibited.

    Evidence Chromatin co-fractionation, alkaline comet assay, transcription inhibition, siRNA in human cells

    PMID:37326017

    Open questions at the time
    • Direct physical interaction between CSB and PARP1/2 not demonstrated with purified proteins
    • Whether HPF1 recruitment is CSB-dependent or PARP-dependent
  18. 2024 High

    Cryo-EM structures of yeast Pol II-Rad26 complexes and functional studies of transcription-coupled DPC repair established the structural basis of CSB/Rad26 recognition of stalled Pol II, and expanded CSB's repair substrates to DNA-protein crosslinks via a non-canonical TC-NER mechanism requiring CRL4^CSA and the proteasome.

    Evidence Cryo-EM structures with biochemical/genetic validation (yeast); DPC-seq, genetic epistasis, transcription restart assays (human)

    PMID:38194460 PMID:38600235 PMID:38600236

    Open questions at the time
    • No cryo-EM structure of human CSB-Pol II complex
    • DPC substrate specificity and size limits for TC-DPC repair unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of human CSB engaged with Pol II on nucleosomal DNA, the precise allosteric mechanism linking autoinhibition relief to lesion-dependent activation, and how CSB's multiple repair and transcription functions are coordinated in time and space in vivo remain unresolved.
  • No human CSB-Pol II cryo-EM structure
  • In vivo single-molecule dynamics of CSB at different damage types not resolved
  • How CSB chooses between TC-NER, TC-BER, TC-HR, and TC-DPC repair pathways at a given lesion

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 5 GO:0003677 DNA binding 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0003723 RNA binding 1
Localization
GO:0005654 nucleoplasm 2 GO:0005694 chromosome 2 GO:0005730 nucleolus 2
Pathway
R-HSA-73894 DNA Repair 10 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 2
Partners
BRCA1ERCC8RAD52RIF1SNM1AUVSSAXPAXRCC1
Complex memberships
CSA-DDB1-CUL4A E3 ligase complexRNA Pol I/TFIIH/XPG nucleolar complexUVSSA-USP7 complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 ERCC6/CSB encodes a 1493 amino acid protein containing seven consecutive helicase motifs (SWI2/SNF2 family) and is required for transcription-coupled nucleotide excision repair (TC-NER), specifically the preferential repair of lesions from the transcribed strand of active genes. Mutation analysis showed the gene is not essential for cell viability but is specific for preferential repair of transcribed sequences. Gene cloning, complementation of CS-B cells, mutation analysis of CS-B patient Cell High 1339317
1990 ERCC6 gene was cloned by complementation of the UV-sensitive CHO mutant UV61 (rodent complementation group 6), which harbors a deficiency in repair of UV-induced cyclobutane pyrimidine dimers but shows apparently normal repair of (6-4) photoproducts. The gene spans ~115 kb of genomic DNA. Genomic DNA transfection, complementation cloning, Southern blot analysis Molecular and cellular biology High 2172786
1993 ERCC6 gene spans 82-90 kb, consists of at least 21 exons, contains seven distinct helicase signature domains encoded on separate exons, and produces two mRNA molecules of 5 and 7 kb via alternative polyadenylation. Genomic organization analysis, cDNA cloning, Northern blot Nucleic acids research High 8382798
1997 Purified recombinant human CSB/ERCC6 protein is a DNA-stimulated ATPase but is not a helicase and does not disrupt the ternary transcription complex of stalled RNA polymerase II. CSB binds DNA and also physically interacts with XPA, TFIIH, and the p34 subunit of TFIIE. Baculovirus overexpression, protein purification, ATPase assay, helicase assay, RNA pol II stalling/dissociation assay, direct binding assays The Journal of biological chemistry High 8999876
1997 CSB/ERCC6 physically interacts with RNA polymerase II engaged in elongation ternary complexes containing DNA and nascent RNA, and this interaction requires ATP hydrolysis (the beta-gamma bond) to form a stable Pol II-CSB-DNA-RNA complex. CSA does not directly bind Pol II. Oligo(dC)-tailed DNA template biochemical assay, ATPase mutant analysis, binding assays Molecular and cellular biology High 9372911
1996 CSB/ERCC6 restores transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers (CPDs) in the transcribed strand of the actively transcribed DHFR gene when transfected into the TCR-deficient CHO cell line UV61, demonstrating that CSB has an independent role in TCR separate from general RNA Pol II transcription. Transfection complementation, strand-specific repair assay (gene-specific repair assay), CPD measurement Nucleic acids research High 8811084
2000 Transcription-coupled repair of 8-oxoguanine requires CSB (as well as XPG and TFIIH). CS-B cells not only lack TCR of 8-oxoG but cannot remove 8-oxoG from a transcribed sequence despite proficient repair elsewhere; unrepaired 8-oxoG blocks RNA polymerase II transcription and leads to a mutation frequency of 30-40% vs normal 1-4%. Strand-specific repair assay, mutation frequency analysis, CS cell lines vs. normal human cells and XP cells Cell High 10786832
2002 CSB is a component of a nucleolar complex (CSB IP/150) that contains RNA pol I, TFIIH, and XPG, and promotes efficient rRNA synthesis. CSB is active in in vitro RNA pol I transcription and restores rRNA synthesis when transfected in CSB-deficient cells. CS-causing mutations in CSB (as well as XPB and XPD) disrupt the RNA pol I/TFIIH interaction within this complex. Immunoprecipitation, in vitro RNA pol I transcription assay, transfection complementation, immunofluorescence (nucleolar localization) Molecular cell High 12419226
2004 GFP-tagged CSB, expressed at physiological levels, is homogeneously dispersed in the nucleoplasm plus bright nuclear foci and nucleolar accumulation. FRAP studies showed GFP-CSB transiently interacts with the transcription elongation machinery as part of a high-molecular-weight complex; upon UV-induced transcription arrest, CSB binding to these complexes is prolonged, consistent with engagement in TC-NER. GFP tagging, live-cell imaging, FRAP (fluorescence recovery after photobleaching) The Journal of cell biology High 15226310
2004 CSB actively wraps DNA around itself in an ATP-dependent manner: scanning force microscopy showed DNA contour length shortening upon CSB binding, consistent with DNA wrapping. Non-hydrolyzable ATP analogues increased the frequency of shorter DNA molecules, suggesting ATP binding promotes wrapping and ATP hydrolysis causes unwrapping. CSB likely binds DNA as a dimer. Scanning force microscopy, ATP and non-hydrolyzable ATP analogue comparison The Journal of biological chemistry High 15548521
2006 CSB is a substrate of the CSA-containing E3 ubiquitin ligase complex: following UV irradiation, CSB is ubiquitinated and degraded by the proteasome in a CSA-dependent manner at a late stage of TC-NER. CSB degradation is required for post-TCR recovery of transcription. Ubiquitination assays, proteasome inhibition, CSA-deficient cells, RNA synthesis recovery assay Genes & development High 16751180
2010 UV-induced stable association of CSB with chromatin requires ATP hydrolysis. The N-terminal region of CSB negatively autoregulates chromatin association during normal growth, and ATP hydrolysis is required to overcome this inhibitory effect. Mutations causing Cockayne syndrome can underlie defects in this chromatin association mechanism. Chromatin fractionation, ATPase mutant analysis, deletion mapping of N-terminal region, UV treatment Molecular cell High 20122405
2003 Mutations in conserved ATPase motifs II, V, and VI of CSB differentially reduce ATPase activity, and dephosphorylation of CSB in vitro results in increased ATPase activity. UV irradiation leads to CSB dephosphorylation in cells, suggesting that phosphorylation status regulates CSB ATPase activity in vivo. Site-directed mutagenesis of helicase motifs, in vitro ATPase assay, phosphorylation analysis Nucleic acids research High 12560492
2012 UVSSA protein forms a complex with USP7, stabilizes ERCC6/CSB protein levels, and restores the hypophosphorylated form of RNA pol II after UV irradiation. Mutations in UVSSA cause UV-sensitive syndrome by destabilizing CSB. Microcell-mediated chromosome transfer (gene cloning), co-immunoprecipitation, complementation assay, western blot for CSB stability Nature genetics High 22466612
2017 CSB displays strong affinity for DNA:RNA hybrids in vitro and acts as a sensor of ROS-induced R loops in transcribed regions. During transcription-coupled homologous recombination (TC-HR), CSB is recruited by R loops, then recruits RAD52 through an acidic domain of CSB, and the CSB-RAD52-RAD51 axis carries out a BRCA1/2-independent alternative HR pathway protecting the transcribed genome. In vitro DNA:RNA hybrid binding assay, ROS-induced R loop induction, laser microirradiation with fluorescent protein foci assay, epistasis with RAD52/BRCA1/BRCA2 knockdown Nature communications High 30297739
2017 ATM-dependent phosphorylation of CSB on S10 and CDK2-dependent phosphorylation on S158 are required for CSB's chromatin remodeling activity at DSBs. CSB interacts via its winged helix domain (WHD) with RIF1, and this interaction mediates CSB recruitment to DSBs in S phase. At DSBs, CSB remodels chromatin by evicting histones, which limits RIF1 and MAD2L2 accumulation but promotes BRCA1 accumulation, thereby regulating DSB repair pathway choice. Co-IP, phospho-specific mutant analysis, chromatin immunoprecipitation, histone eviction assay, DSB repair pathway choice analysis Nature communications High 29203878
2019 CSB interacts with the BRCT domain of BRCA1 in a CDK-dependent manner (phosphorylation on S1276), peaking in late S/G2 phase. This interaction mediates CSB's association with the BRCA1-C complex (BRCA1, MRN, CtIP). CSB phosphorylation on S1276 promotes MRN- and CtIP-mediated DNA end resection for HR and restricts NHEJ, while being dispensable for histone eviction at DSBs. Co-IP, CDK inhibitor treatment, phospho-mutant analysis, DNA end resection assay, cell survival assay Nucleic acids research High 31501894
2018 CSB stimulates recruitment of XRCC1 (a BER-scaffolding protein) to 8-oxoG lesions in a transcription-dependent manner. OGG1 recruitment to 8-oxoG is independent of CSB. XRCC1 recruitment to BER-unrelated single-strand breaks does not require CSB, suggesting CSB specifically facilitates BER progression at transcribed genes by recruiting XRCC1 to BER-generated SSBs masked by stalled RNA polymerase II. Live-cell imaging with laser-assisted local induction of 8-oxoG, fluorescent protein recruitment kinetics, CSB knockdown and knockout cells Nucleic acids research High 29955842
2021 CSB loads the PAF1 complex (PAF1C) onto RNA polymerase II in promoter-proximal regions in response to DNA damage. PAF1C is dispensable for TCR-mediated repair but is essential for transcription recovery after UV irradiation by promoting RNAPII pause release in promoter-proximal regions and acting as a processivity factor for transcription elongation throughout genes. Co-IP, ChIP-seq, mass spectrometry, RNA recovery assays after UV, PAF1C knockdown, UV survival Nature communications High 33637760
2024 CSB and CSA are required for transcription-coupled DNA-protein crosslink (DPC) repair in actively transcribed genes. DPC formation arrests transcription, and CSB/CSA-deficient cells fail to efficiently restart transcription after DPC induction. Downstream TC-NER factors (XPA etc.) are dispensable, indicating a non-canonical TC-NER mechanism for DPCs. TC-DPC repair is mediated by the ubiquitin ligase CRL4CSA and the proteasome. DPC sequencing (genome-wide DPC mapping), genetic screens, transcription restart assays, cell survival assays, epistasis with NER factors Nature cell biology High 38600235 38600236
2008 CSB expression is directly regulated by HIF-1; CSB mutant cells fail to properly activate the HIF-1 pathway under hypoxia. CSB redistributes p300 between HIF-1 and p53, functioning in a feedback loop that modulates p53 biological functions during hypoxic response. Reporter assays, ChIP, co-immunoprecipitation, CSB-deficient cell analysis, HIF-1 pathway activation assays The EMBO journal Medium 18784753
2011 CSB and CSA associate in a unique complex with p53 and Mdm2 (a Cullin Ring Ubiquitin Ligase complex), and this interaction greatly stimulates Mdm2-dependent ubiquitination of p53. Absence of CSB leads to elevated and persistent p53 levels due to insufficient ubiquitination. Co-IP, tandem affinity purification, mass spectrometry, ubiquitination assays, CS patient cell analysis Cell cycle Medium 22032989
2014 CSB directly interacts with SNM1A (a 5'-3' exonuclease), modulates SNM1A's exonuclease activity on oligonucleotide substrates in vitro, and co-exists with SNM1A in a common complex in human cell extracts. Both proteins are recruited to trioxsalen-induced interstrand crosslink (ICL) damage in transcription-dependent manner; SNM1A recruitment is reduced in CSB-deficient cells. CSB-deficient neural cells show increased sensitivity to crosslinking agents and delayed ICL processing. Yeast two-hybrid, purified recombinant protein interaction, in vitro exonuclease assay, Co-IP from cell extracts, laser microirradiation + fluorescence microscopy, comet assay, γ-H2AX foci Nucleic acids research High 25505141
2016 VCP/p97 segregase mediates UV-induced ubiquitin-mediated CSB degradation. VCP/p97 interacts with both native and ubiquitin-conjugated forms of CSB, and VCP/p97 cofactors UFD1 and UBXD7 are required for CSB degradation. VCP/p97 associates with the CSA-DDB1-Cul4A E3 ligase complex. Inhibition of VCP/p97 causes accumulation of ubiquitinated CSB in chromatin and unexpectedly enhances recovery of RNA synthesis following UV. Co-IP, VCP/p97 inhibitors, siRNA depletion, localized UV irradiation with foci analysis, RNA synthesis recovery assay The Journal of biological chemistry Medium 26826127
2017 NAP1L1 histone chaperone interacts with CSB and enhances CSB-mediated nucleosome remodeling. Single-molecule analysis showed CSB remodels nucleosomes via three phases (activation, translocation, pausing), and NAP1L1 accelerates both activation and translocation phases and decreases pausing probability, thereby increasing processivity. Single-molecule FRET/fluorescence microscopy, ATPase assay, in vitro nucleosome remodeling assay Nucleic acids research High 28369616
2014 A conserved 'leucine latch' motif at the N terminus of Rhp26 (S. pombe ortholog of CSB/ERCC6) mediates autoinhibition of ATPase and chromatin-remodeling activities via interaction with the core ATPase domain. The C terminus counteracts this autoinhibition; both N- and C-terminal regions are needed for proper DNA repair function in vivo. Mutagenesis, in vitro ATPase assay, nucleosome remodeling assay, in vivo DNA repair assay, protein interaction studies Proceedings of the National Academy of Sciences of the United States of America High 25512493
2020 ROS-induced DNA damage at telomeres triggers R-loop accumulation in a TERRA- and TRF2-dependent manner. CSB and RAD52 are recruited to telomeric R-loops; RAD52 is recruited through interactions with both CSB and DNA:RNA hybrids. Both CSB and RAD52 are required for efficient repair of ROS-induced telomeric DSBs through a CSB-RAD52-POLD3-mediated break-induced replication pathway. Live-cell imaging, ChIP, immunoprecipitation, knockdown of CSB/RAD52/POLD3, R-loop detection (S9.6 antibody), comet assay Nucleic acids research High 31777915
2020 CSB promotes recruitment of HR repair proteins (MRN, BRCA1, BLM, RPA32) and POLD3 to ALT telomeres via its ATPase activity (controlled by ATM- and CDK2-dependent phosphorylation). Loss of CSB stimulates telomeric recruitment of MUS81 and SLX4 (MUS-SLX endonuclease complex), suggesting CSB restricts MUS-SLX-mediated processing of stalled forks at ALT telomeres. Fluorescence imaging with tagged proteins, phospho-mutant analysis, epistasis with SMARCAL1 depletion, ATM/CDK2 inhibitor treatment Journal of cell science Medium 31974116
2023 CSB regulates PARP1- and PARP2-mediated single-strand break repair (SSBR) at actively transcribed DNA regions. PARP1 and PARP2 promote CSB recruitment to oxidatively-damaged DNA; CSB in turn promotes XRCC1 and HPF1 recruitment and histone PARylation. CSB's function in SSBR is bypassed when transcription is inhibited, showing CSB-mediated SSBR occurs primarily at actively transcribed regions. Chromatin co-fractionation, alkaline comet assay, transcription inhibition, siRNA depletion, immunofluorescence Nucleic acids research Medium 37326017
2008 CSB gene contains a domesticated PiggyBac-like transposon (PGBD3) in intron 5 that functions as an alternative 3' terminal exon, producing a CSB-PGBD3 fusion protein by alternative splicing of CSB exons 1–5 to the PGBD3 transposase. This fusion protein is as abundant as CSB protein in various human cell lines and continues to be expressed in CS cells with mutations beyond exon 5. RT-PCR, western blot, expression analysis in multiple cell lines, evolutionary conservation analysis PLoS genetics High 18369450
2015 CSB mutant (CS patient) cells, but not UVSS cells, show depletion of mitochondrial DNA polymerase-γ catalytic subunit (POLG1) due to CSA/CSB-dependent accumulation of HTRA3 serine protease. Inhibition of serine proteases restored POLG1 levels in CS fibroblasts. CS cells showed greater nitroso-redox imbalance and altered mitochondrial oxidative phosphorylation compared to UVSS cells. Western blot, siRNA depletion of CSB, serine protease inhibitors, ROS scavengers, mitochondrial OXPHOS measurement Proceedings of the National Academy of Sciences of the United States of America Medium 26038566
2015 CSB directly interacts with CTCF in vitro, and oxidative stress enhances the CSB-CTCF interaction in cells. CSB facilitates CTCF-DNA interactions in vitro and regulates CTCF-chromatin interactions in oxidatively stressed cells. Oxidative stress alters CSB's genomic occupancy and increases CSB occupancy at promoters, with CTCF regulating sites of CSB occupancy. ChIP-seq, in vitro protein interaction assay, co-IP from cells, oxidative stress treatment Nucleic acids research Medium 26578602
2024 Cryo-EM structures of yeast Pol II-Rad26 complexes (ortholog of CSB) show that Rad26 uses a common mechanism to recognize stalled Pol II, with additional interactions when Pol II is arrested at a DNA lesion. Elf1 (ortholog of human ELOF1) induces further interactions between Rad26 and lesion-arrested Pol II. Biochemical and genetic data show that interplay between Elf1 and Rad26 is important for TC-NER initiation. Cryo-EM structure determination, biochemical assays, genetic analysis in yeast Proceedings of the National Academy of Sciences of the United States of America High 38194460
1994 RAD26, the S. cerevisiae ortholog of ERCC6/CSB, is required for preferential TCR of UV-induced cyclobutane pyrimidine dimers from the transcribed strand of the active RBP2 gene. Disruption of RAD26 does not cause UV sensitivity (unlike human CSB mutations), indicating TCR in lower eukaryotes is not critical for cell survival. Gene cloning, RAD26 disruption mutant, strand-specific repair assay, UV/cisplatin/X-ray sensitivity testing The EMBO journal High 7957102
1996 Purified yeast Rad26 protein (ortholog of human CSB) is a DNA-dependent ATPase that is much more active and strictly DNA-dependent compared to the E. coli Mfd protein, suggesting Rad26 may displace stalled RNA pol II or recruit repair components at DNA lesions. Yeast protein purification, in vitro ATPase assay The Journal of biological chemistry High 8702468
2002 Yeast Def1 forms a complex with Rad26 (CSB ortholog) in chromatin. In response to DNA damage, Rad26 promotes TCR while Def1 is required for ubiquitination and degradation of stalled RNA polymerase II (RNAPII) when lesions cannot be rapidly removed, providing a coordinated rescue mechanism for Pol II stalled at DNA lesions. Protein complex identification, genetic analysis, RNAPII ubiquitination assay, chromatin fractionation Nature High 11859374
2006 CSB plays a general role in chromatin maintenance and remodeling: genes regulated by CSB overlap significantly with genes affected by HDAC inhibitors, DNA methylation inhibitors, PARP inhibitors, and RNA pol II elongation inhibitors. CSB-null cells are sensitive to HDAC and PARP inhibitors, indicating CSB has broad chromatin maintenance functions beyond TC-NER. Expression microarrays, comparative L2L analysis, drug sensitivity assays (HDAC and PARP inhibitors) Proceedings of the National Academy of Sciences of the United States of America Medium 16772382

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet (London, England) 1118 33545094
2004 GMD@CSB.DB: the Golm Metabolome Database. Bioinformatics (Oxford, England) 945 15613389
2020 Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet (London, England) 686 32896291
1992 ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne's syndrome and preferential repair of active genes. Cell 656 1339317
1996 Role of CSB/p38/RK stress response kinase in LPS and cytokine signaling mechanisms. Journal of leukocyte biology 348 8603987
2000 Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome. Cell 272 10786832
1994 RAD26, the functional S. cerevisiae homolog of the Cockayne syndrome B gene ERCC6. The EMBO journal 229 7957102
1997 Human transcription-repair coupling factor CSB/ERCC6 is a DNA-stimulated ATPase but is not a helicase and does not disrupt the ternary transcription complex of stalled RNA polymerase II. The Journal of biological chemistry 220 8999876
2006 CSA-dependent degradation of CSB by the ubiquitin-proteasome pathway establishes a link between complementation factors of the Cockayne syndrome. Genes & development 213 16751180
2000 The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. Genes & development 199 10950868
2012 Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. Nature genetics 188 22466612
2002 A Rad26-Def1 complex coordinates repair and RNA pol II proteolysis in response to DNA damage. Nature 188 11859374
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