{"gene":"XPC","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2007,"finding":"Crystal structure of yeast XPC orthologue Rad4 bound to CPD-containing DNA reveals that Rad4 inserts a β-hairpin through the DNA duplex, causing the two damaged base pairs to flip out of the double helix; the expelled nucleotides of the undamaged strand are recognized by Rad4 while the CPD-linked nucleotides become disordered, indicating XPC/Rad4 recognizes lesion-induced helix destabilization rather than the lesion chemistry itself.","method":"X-ray crystallography of Rad4-DNA complex with CPD lesion","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of Rad4/XPC bound to damaged DNA with direct structural validation of the flipping mechanism","pmids":["17882165"],"is_preprint":false},{"year":2005,"finding":"UV irradiation induces reversible polyubiquitylation of XPC, dependent on functional UV-DDB activity. XPC and UV-DDB interact physically, and both are polyubiquitylated by the recombinant UV-DDB-ubiquitin ligase complex (CRL4-DDB2). Ubiquitylation alters the DNA-binding properties of XPC and UV-DDB and is required for cell-free NER of UV-induced (6-4) photoproducts specifically when UV-DDB is bound to the lesion, supporting a model in which ubiquitylation transfers lesion recognition from UV-DDB to XPC.","method":"Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant UV-DDB-ubiquitin ligase complex, cell-free NER assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted ubiquitylation in vitro, functional NER assay, reciprocal co-IP, multiple orthogonal methods in a single rigorous study","pmids":["15882621"],"is_preprint":false},{"year":2005,"finding":"XPC protein is modified by both SUMO-1 and ubiquitin following UV irradiation in mammalian cells. These modifications require the functions of DDB2 and XPA. Sumoylation of XPC protects it from proteasomal degradation, as XPC is significantly degraded in XP-A cells where sumoylation does not occur.","method":"Western blot, reciprocal immunoprecipitation, siRNA knockdown, NER-deficient cell lines, proteasome inhibitor treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with siRNA validation, single lab, multiple orthogonal methods","pmids":["16030353"],"is_preprint":false},{"year":1996,"finding":"XPC protein forms a tight complex with HHR23B. Both XPC alone and the XPC-HHR23B heterodimer bind DNA with high affinity and prefer UV-damaged DNA. XPC alone (without HHR23B) is sufficient for reconstitution of human excision nuclease activity in vitro; HHR23B has no detectable additional effect on excision activity.","method":"Recombinant protein overexpression/purification, in vitro DNA binding assays, reconstituted human excision nuclease assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins demonstrating XPC sufficiency for excision nuclease activity","pmids":["8702634"],"is_preprint":false},{"year":2015,"finding":"RNF111 (a SUMO-targeted ubiquitin ligase) promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. This ubiquitylation promotes the release of XPC from damaged DNA after NER initiation and is required for stable incorporation of the NER endonucleases XPG and ERCC1/XPF, establishing sequential XPC ubiquitylation by CRL4(DDB2) and RNF111 as a quality-control mechanism for NER progression.","method":"Live-cell imaging, siRNA knockdown, immunoprecipitation, ubiquitylation assays, NER repair assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, co-IP, functional NER assay), demonstrated direct mechanistic consequence of ubiquitylation for downstream factor recruitment","pmids":["26151477"],"is_preprint":false},{"year":2015,"finding":"Tripartite damage verification in NER: XPC initially detects lesions and recruits TFIIH; bulky lesions inhibit the ATPase and helicase activities of XPB and XPD in the TFIIH core (Core7), promoting NER. XPA activates unwinding of normal DNA by Core7 but inhibits Core7 helicase activity in the presence of bulky lesions. The CAK module of TFIIH inhibits DNA binding by TFIIH and enhances XPC-dependent specific recruitment of TFIIH.","method":"In vitro ATPase and helicase assays with purified human ten-subunit TFIIH and Core7, defined substrate specificity experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemical assays with purified homogeneous human TFIIH, multiple enzyme activity measurements","pmids":["26384665"],"is_preprint":false},{"year":2006,"finding":"The yeast damage-recognition heterodimer Rad4-Rad23 physically interacts with SWI/SNF chromatin-remodeling complex subunits Snf6 and Snf5; this interaction is stimulated by UV irradiation. SWI/SNF is required for efficient NER at the transcriptionally silent HML locus and mediates UV-induced nucleosome rearrangement at that locus, linking XPC/Rad4-mediated damage recognition to ATP-dependent chromatin remodeling.","method":"Co-purification of SWI/SNF with Rad4-Rad23, genetic analysis in SWI/SNF mutants, restriction enzyme accessibility assay for nucleosome remodeling","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-purification of complex plus functional NER assay in chromatin plus nucleosome remodeling assay, multiple orthogonal methods","pmids":["17013386"],"is_preprint":false},{"year":2012,"finding":"RAD23 proteins facilitate damage recognition by XPC but dissociate rapidly from XPC upon XPC binding to UV-induced DNA lesions. In the absence of RAD23, XPC association with UV-induced lesions is impaired. RAD23 does not participate in downstream NER events after damage recognition.","method":"Live-cell fluorescence microscopy, siRNA knockdown, UV damage localization assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with siRNA knockdown, single lab, direct visualization of XPC-RAD23 dynamics at damage sites","pmids":["22431748"],"is_preprint":false},{"year":2004,"finding":"Rad23 stabilizes Rad4 from proteasomal degradation through a specific short amino acid motif. Ubiquitin-conjugating enzymes Ubc4 and Ubc5 and the proteasome regulate Rad4 levels. Rad23's role in stabilizing Rad4 is independent of its role in proteasome interaction (via UbL domain), as demonstrated by complementation with separation-of-function mutants.","method":"Genetic analysis, protein stability assays, complementation with Rad23 separation-of-function mutants in yeast","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with separation-of-function mutants, single lab, well-controlled yeast genetics","pmids":["15601997"],"is_preprint":false},{"year":2014,"finding":"The p97/VCP/Cdc48 segregase complex is required for timely extraction of DDB2 and XPC from chromatin after UV damage. Prolonged retention of DDB2 and XPC in chromatin due to loss of p97 impairs DNA excision repair and leads to chromosomal aberrations. Concomitant downregulation of DDB2 or XPC rescues genome instability in p97-deficient cells.","method":"Chromatin fractionation, siRNA knockdown of p97, UV-lesion repair assays, chromosomal aberration analysis, epistasis experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, repair assays, genetic rescue), direct mechanistic link between p97-mediated extraction and XPC function","pmids":["24770583"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Rad4 (yeast XPC) tethered to undamaged DNA (via disulfide crosslink) shows that Rad4 can flip out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Temperature-jump perturbation spectroscopy reveals kinetics of lesion opening. Results support a kinetic gating mechanism for damage recognition whereby lesion selectivity arises from kinetic competition between DNA opening and Rad4's residence time per site.","method":"X-ray crystallography of disulfide-tethered Rad4-DNA complex on undamaged DNA, temperature-jump perturbation spectroscopy","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biophysical kinetic measurements, multiple orthogonal methods in one study","pmids":["25562780"],"is_preprint":false},{"year":2016,"finding":"Single-molecule fluorescence microscopy of quantum dot-labeled Rad4-Rad23 (yeast XPC-RAD23B) shows three types of 1D motion on DNA: non-motile, random diffusion, and constrained. Deletion of BHD3's β-hairpin tip increases constrained motion at the expense of stable lesion binding, without abolishing damage-specific binding or cellular UV resistance, indicating this motif is needed for stable lesion engagement but not for initial damage detection.","method":"Single-molecule fluorescence microscopy, quantum dot labeling, atomic force microscopy, in vivo UV resistance assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — single-molecule imaging plus AFM plus in vivo genetic validation, multiple orthogonal methods","pmids":["27720644"],"is_preprint":false},{"year":2016,"finding":"Temperature-jump spectroscopy reveals a two-step 'twist-open' mechanism for Rad4/XPC lesion recognition: an early ~100–500 μs step corresponding to nonspecific DNA unwinding/twisting, followed by a ~10 ms rate-limiting step of nucleotide flipping/opening. The β-hairpin is not required for DNA unwinding but is essential for full nucleotide flipping.","method":"Temperature-jump perturbation spectroscopy with fluorescence detection, mutagenesis of β-hairpin domain","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biophysical reconstitution with mutagenesis, directly captures kinetics of the recognition mechanism","pmids":["27035942"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of Rad4-Rad23 (yeast XPC-Rad23B) bound to 6-4PP-containing DNA shows that Rad4 flips out both nucleotide pairs containing the 6-4PP, forming an 'open' conformation. Molecular dynamics simulations show Rad4 initiates engagement via BHD2 bending/untwisting from the minor groove, with stepwise extrusion of the base pairs. CPD resists such Rad4-induced distortions, explaining the differential repair efficiency.","method":"X-ray crystallography, molecular dynamics simulations (4 μs)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of Rad4/XPC with physiological substrate complemented by extensive MD simulations","pmids":["31106376"],"is_preprint":false},{"year":2019,"finding":"Human XPC-RAD23B diffuses along DNA via hopping (ionic-strength-dependent), allowing bypass of protein obstacles during lesion search. XPC-RAD23B makes futile attempts to bind CPDs, and binds CPDs in two states: stable (lesion recognition) and transient (interrogation), consistent with low CPD recognition efficiency.","method":"Single-molecule fluorescence imaging on tethered DNA, analysis of diffusion coefficients vs. ionic strength","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-molecule imaging of human XPC-RAD23B, single lab, direct mechanistic characterization of search dynamics","pmids":["31372632"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of human XPC-TFIIH-XPA on damaged DNA reveal the mechanism of lesion hand-off: XPA binds between XPB and XPD, kinks the DNA duplex, and shifts XPC and the DNA lesion by nearly a helical turn relative to TFIIH Core7, positioning the lesion outside Core7. XPB and XPD, tracking the lesion-containing strand in opposite directions, push and pull the lesion strand into XPD for verification.","method":"Cryo-EM structural determination of human XPC-TFIIH-XPA complex on damaged DNA","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures directly capturing multiple intermediates of lesion handoff from XPC to TFIIH/XPA","pmids":["37076618"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of TFIIH/Rad4-Rad23-Rad33 on a carcinogen-DNA adduct lesion (3.9–9.2 Å resolution) shows ~30 bp DNA straddling between Rad4 and the Ssl2 (XPB) subunit of TFIIH, with DNA unwinding at the lesion site. Simultaneous binding of Rad4 and TFIIH is enabled by unwinding at the lesion. Ssl2 translocation coupled with torque would extend DNA unwinding and deliver the damaged strand to Rad3 (XPD) in an open form for lesion scanning.","method":"Cryo-EM structure determination of Rad4-Rad23-Rad33/TFIIH complex on DNA","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure of the NER initiation complex directly revealing the architecture of Rad4/XPC-TFIIH co-engagement on damaged DNA","pmids":["34099686"],"is_preprint":false},{"year":2017,"finding":"PARP1 forms a stable complex with XPC in the nucleoplasm under steady-state conditions and directly escorts XPC to UV-induced DNA lesions after irradiation in a DDB2-independent manner. PARP1 catalytic activity is not required for initial XPC complex formation but enhances XPC recruitment to lesion sites. Purified PARP1-XPC complex facilitates handover of XPC to the UV-lesion site in the presence of the UV-DDB ligase complex.","method":"Co-immunoprecipitation, live-cell imaging, in vitro pull-down with purified proteins, UV irradiation experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and purified protein reconstitution, single lab, multiple supporting experiments","pmids":["28760956"],"is_preprint":false},{"year":2022,"finding":"PARP1 and PARP2 are constitutive interactors of XPC. XPC stimulates PARP1 synthesis of poly-(ADP-ribose) (PAR) at UV lesions, enabling recruitment and activation of the chromatin remodeler ALC1. PARP2 modulates ALC1 retention at damage sites. ALC1 mediates chromatin expansion at UV-induced lesions, promoting timely repair of CPDs.","method":"Mass spectrometry interactomics, Co-IP, live-cell imaging, PAR synthesis assays, chromatin remodeling assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP, functional PAR synthesis assay, chromatin remodeling assay, mechanistic epistasis; multiple orthogonal methods","pmids":["35963869"],"is_preprint":false},{"year":1994,"finding":"Yeast Rad4 protein physically interacts with TFIIH (factor b) in vitro, suggesting Rad4/XPC directly recruits TFIIH as part of NER repairosome assembly.","method":"In vitro binding assay of Rad4 with purified TFIIH (factor b) subunits","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding with purified TFIIH, early foundational experiment, single lab","pmids":["8196602"],"is_preprint":false},{"year":2004,"finding":"NEF4 (containing Rad7, Rad16 ATPase, and Elc1) regulates Rad4 protein levels; mutations in NEF4 or the E2 enzyme Ubc13 result in elevated Rad4 levels and increased ubiquitylated Rad23 species, establishing that NEF4 controls Rad4 turnover through a ubiquitin ligase mechanism.","method":"Genetic mutant analysis in yeast, protein level measurements, ubiquitylation detection by Western blot","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with direct protein-level measurements, single lab","pmids":["15226437"],"is_preprint":false},{"year":2010,"finding":"Yeast deubiquitinase Ubp3 physically interacts with Rad4 and the 26S proteasome (both in vivo and in vitro) and facilitates Rad4 degradation. Disruption of UBP3 increases UV resistance and Rad4 levels, especially in rad23Δ cells. Catalytically inactive Ubp3-C469A cannot affect NER or Rad4 levels.","method":"Co-immunoprecipitation in vivo and in vitro, yeast genetic analysis, UV sensitivity assays, protein stability measurements","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus active site mutant confirmation plus genetic analysis, single lab","pmids":["20876584"],"is_preprint":false},{"year":2008,"finding":"GFP-tagged XPC continuously associates with and dissociates from chromatin in undamaged cells. UV damage retards XPC mobility (shown by FRAP). XPC undergoes continuous nuclear export and import under basal conditions, which is blocked when NER lesions are present. This nucleus-cytoplasm shuttling controls steady-state nuclear XPC levels and allows concentration increases under genotoxic stress.","method":"FRAP (fluorescence recovery after photobleaching), live-cell imaging of GFP-XPC, nuclear-cytoplasmic fractionation","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell FRAP and imaging directly demonstrating shuttling and damage-dependent retention, single lab","pmids":["18682493"],"is_preprint":false},{"year":2008,"finding":"Yeast Rad33 directly binds Rad4 via the same conserved amino acids required for the interaction of human XPC with Centrin2. The Rad4-Rad33 interaction prevents UV-induced Rad4 modification; disruption of this interaction enhances Rad4 modification (dependent on TCR factor Rad26) and causes a repair defect.","method":"Direct binding assays, mutational analysis of Rad4-Rad33 interaction interface, yeast genetic analysis, UV repair assays","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by mutagenesis, genetic rescue experiments, single lab","pmids":["18387345"],"is_preprint":false},{"year":2015,"finding":"The XPC-RAD23B-CETN2 complex functions as a stem cell coactivator (SCC) required for OCT4/SOX2 transcriptional activation in embryonic stem cells. XPC is identified as the subunit essential for interaction with OCT4 and SOX2, and SCC binds regulatory regions of pluripotency genes. OCT4 and SOX2 are the primary transcription factors recruiting SCC to these promoters.","method":"Genome-wide ChIP-seq mapping of RAD23B, transcriptional profiling of SCC-depleted ESCs, co-immunoprecipitation of XPC with OCT4/SOX2","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus Co-IP with defined subunit requirement, single lab, two orthogonal approaches","pmids":["25901318"],"is_preprint":false},{"year":2018,"finding":"In undamaged cells, XPC co-localizes with RNA Pol II and active histone modification marks at a subset of class II promoters. XPC depletion reduces H3K9 acetylation and pre-initiation complex formation at target genes. XPC physically interacts with the histone acetyltransferase KAT2A and recruits the KAT2A-containing ATAC complex to promoters. XPC also interacts with E2F1 and promotes E2F1 binding to its DNA element at target promoters.","method":"ChIP-seq, RNA-seq, co-immunoprecipitation of XPC with KAT2A and E2F1, histone modification assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus Co-IP confirming XPC-KAT2A and XPC-E2F1 interactions, single lab, multiple orthogonal methods","pmids":["29973595"],"is_preprint":false},{"year":2017,"finding":"XPC DNA repair complex cooperates with TDG genome-wide to stimulate turnover of TDG-abasic site intermediates during active DNA demethylation, overcoming slow TDG product dissociation. XPC-induced DNA demethylation in somatic cells facilitates cellular reprogramming and generation of more robust iPSCs.","method":"Genome-wide methylation analysis, biochemical TDG turnover assays, iPSC reprogramming experiments, Co-IP","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical TDG activity assay plus genome-wide methylation profiling, single lab","pmids":["28512237"],"is_preprint":false},{"year":2010,"finding":"XPC complex stimulates the enzymatic turnover of TDG (thymine DNA glycosylase) by promoting TDG displacement from its abasic-site product, and also stimulates sumoylated TDG and SMUG1 activities. XPC effects on E. coli TDG homolog (EcMUG) are only marginal; EcMUG does not significantly interact with XPC. Physical interaction between XPC and the glycosylase is required for stimulation of glycosylase activity.","method":"In vitro glycosylase activity assays, protein-protein interaction assays, comparison of XPC effects on human vs. E. coli TDG homologs","journal":"Journal of nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assays with direct binding controls, single lab","pmids":["20798892"],"is_preprint":false},{"year":2013,"finding":"XPC participates in MDM2-mediated p53 degradation via direct interaction with MDM2. p53 remains ubiquitylated in XPC-deficient cells but its association with the proteasome is drastically reduced, indicating XPC regulates a postubiquitylation step. The pathogenic XPC W690S mutant is specifically defective for MDM2 binding and p53 degradation. XPC overexpression renders p53 unstable even after UV irradiation.","method":"Co-immunoprecipitation, protein stability assays, XPC mutant analysis, proteasome association assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus pathogenic mutant analysis plus functional proteasome association assay, single lab","pmids":["24258024"],"is_preprint":false},{"year":2017,"finding":"USP11 deubiquitylates XPC and promotes its retention at DNA damage sites. UV irradiation induces USP11 recruitment to chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner. USP11 positively regulates NER capacity.","method":"Co-immunoprecipitation, chromatin fractionation, deubiquitylation assays, NER activity assays, UV irradiation experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deubiquitylation assay plus functional NER measurement, single lab","pmids":["29228550"],"is_preprint":false},{"year":2009,"finding":"Rad4 (yeast XPC) regulates proteasomal degradation of ubiquitylated substrates at a postubiquitylation step. Rad4 and Rad23 share common substrates; substrates in rad4Δ cells remain ubiquitylated. Rad4 participates in the Rad23-Ufd2 proteolytic pathway. Upon DNA damage, Rad4 concentrates in the nucleus and degradation of non-nuclear substrate Pex29 is compromised, suggesting coordination between DNA repair and proteolysis.","method":"Yeast genetic deletion analysis, ubiquitylation assays, substrate degradation assays, cellular fractionation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with direct protein degradation measurements, single lab","pmids":["19889839"],"is_preprint":false},{"year":2007,"finding":"Human XPC-HR23B exhibits lesion-specific patterns of DNA helix opening (detected by permanganate footprinting) that differ among three stereoisomeric B[a]P-N2-dG lesions and differ from cisplatin adducts. The extent of helix distortion and overall XPC/HR23B binding to double-stranded DNA containing these lesions correlates with dual incisions by reconstituted NER.","method":"Permanganate footprinting assay, electrophoretic mobility shift assay (EMSA), reconstituted NER incision assay with six purified factors","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — reconstituted NER incision assay with purified factors plus footprinting, single lab","pmids":["17525733"],"is_preprint":false},{"year":1998,"finding":"The yeast Rad4-Rad23 complex binds preferentially to UV-irradiated and AAF-treated damaged DNA over undamaged DNA, as demonstrated by gel mobility shift assays. The complex complements in vitro NER defects of rad4 and rad23 mutant extracts.","method":"Affinity-purified epitope-tagged Rad4-Rad23, EMSA, in vitro NER complementation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding preference demonstrated with complementation validation, single lab","pmids":["9837874"],"is_preprint":false},{"year":1996,"finding":"The majority of HHR23B exists in a free, non-complexed form, while a minor fraction is tightly associated with XPC. HHR23A is not detected in complex with XPC. Immunofluorescence studies show XPC, HHR23B, and HHR23A all reside in the nucleus.","method":"Heparin chromatography, gel filtration, native gel electrophoresis, immunodepletion, immunofluorescence","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical fractionation methods and immunolocalization, single lab","pmids":["8692695"],"is_preprint":false},{"year":2015,"finding":"Single-particle electron microscopy of the human holo-XPC complex (XPC-RAD23B-CETN2) reveals a flexible, ear-shaped structure that undergoes localized loss of order upon DNA binding. The yeast Rad4 holo-complex has similar overall architecture. Subunit positions were mapped by tagging and deletion experiments.","method":"Single-particle electron microscopy, subunit tagging and deletion mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — EM structure with biochemical subunit mapping, single lab","pmids":["26627236"],"is_preprint":false}],"current_model":"XPC (yeast ortholog Rad4) is the primary damage sensor for global genome NER: it interrogates DNA via a stepwise 'twist-open' kinetic gating mechanism, inserting a β-hairpin to flip out two destabilized base pairs (recognizing the undamaged strand opposite the lesion), then recruits TFIIH and XPA for tripartite damage verification with lesion hand-off coordinated by XPA-induced DNA kinking; XPC is regulated by sequential ubiquitylation (CRL4-DDB2, then RNF111/SUMO) that controls its release from damaged DNA to permit downstream factor assembly, by RAD23-mediated stabilization from proteasomal degradation, by PARP1-mediated escort to lesions, and by p97-dependent chromatin extraction; beyond NER, XPC stimulates TDG glycosylase activity and TDG-mediated DNA demethylation, participates in MDM2-mediated p53 proteolysis, recruits the ATAC/KAT2A acetyltransferase complex to promoters via interaction with E2F1, and engages PARP1/2 to recruit the chromatin remodeler ALC1 for repair of difficult-to-detect lesions."},"narrative":{"mechanistic_narrative":"XPC is the primary damage sensor for global-genome nucleotide excision repair (NER), recognizing lesions indirectly through the helix destabilization they impose rather than through lesion chemistry itself [PMID:17882165, PMID:8702634]. Structural and biophysical work establishes that XPC (and its yeast ortholog Rad4) interrogates DNA by a two-step 'twist-open' mechanism—a fast nonspecific unwinding/untwisting step followed by a rate-limiting nucleotide-flipping step in which a β-hairpin is inserted through the duplex to expel two destabilized base pairs and engage the undamaged strand opposite the lesion [PMID:17882165, PMID:27035942, PMID:31106376]; lesion selectivity arises from kinetic gating, the competition between the rate of DNA opening and XPC's residence time at each site, which explains why readily distorted 6-4 photoproducts are recognized far more efficiently than rigid CPDs [PMID:25562780, PMID:31106376, PMID:31372632]. XPC functions as a heterodimer with HHR23B/RAD23, which facilitates damage recognition and protects XPC from proteasomal degradation but dissociates upon stable lesion engagement and plays no role in downstream NER [PMID:8702634, PMID:22431748, PMID:15601997]. Once bound, XPC directly recruits TFIIH and hands the lesion off for tripartite verification: XPA binds between XPB and XPD, kinks the duplex, and shifts XPC and the lesion relative to the TFIIH core so that XPB and XPD track the damaged strand in opposite directions and feed it into XPD for scanning [PMID:37076618, PMID:34099686, PMID:8196602, PMID:26384665]. XPC engagement and turnover are controlled by sequential ubiquitylation—by CRL4(DDB2), which transfers lesion recognition from UV-DDB to XPC, and then by the SUMO-targeted ligase RNF111, whose K63-linked ubiquitylation releases XPC from damaged DNA to permit stable loading of the XPG and ERCC1/XPF endonucleases—together with p97/VCP-mediated chromatin extraction, deubiquitylation by USP11, and SUMO-mediated stabilization [PMID:15882621, PMID:16030353, PMID:26151477, PMID:24770583, PMID:29228550]. XPC also couples lesion recognition to chromatin remodeling, recruiting SWI/SNF and, via PARP1/PARP2-dependent PAR synthesis, the remodeler ALC1 to expand chromatin at difficult-to-detect lesions [PMID:17013386, PMID:28760956, PMID:35963869]. Beyond NER, XPC moonlights in transcription and genome maintenance: as part of an XPC-RAD23B-CETN2 stem-cell coactivator it supports OCT4/SOX2-driven pluripotency gene expression [PMID:25901318], it recruits the KAT2A/ATAC acetyltransferase complex to promoters through E2F1 [PMID:29973595], it stimulates TDG glycosylase turnover during active DNA demethylation [PMID:28512237, PMID:20798892], and it promotes MDM2-mediated proteasomal degradation of p53 at a post-ubiquitylation step [PMID:24258024].","teleology":[{"year":1994,"claim":"Establishing how the NER initiator connects to downstream machinery, Rad4/XPC was shown to physically contact TFIIH, defining it as the factor that nucleates repairosome assembly.","evidence":"In vitro binding of yeast Rad4 with purified TFIIH (factor b)","pmids":["8196602"],"confidence":"Medium","gaps":["Did not define the structural basis or stoichiometry of the Rad4-TFIIH contact","Interaction shown in yeast, not yet for human XPC"]},{"year":1996,"claim":"Defining XPC's composition and biochemical sufficiency, XPC was shown to form a tight heterodimer with HHR23B, bind preferentially to UV-damaged DNA, and be sufficient alone to reconstitute excision activity.","evidence":"Recombinant protein purification, in vitro DNA-binding and reconstituted human excision nuclease assays; biochemical fractionation/immunolocalization","pmids":["8702634","8692695"],"confidence":"High","gaps":["Did not explain how XPC discriminates damaged from undamaged DNA at atomic resolution","Functional role of HHR23B not clarified by the excision assay"]},{"year":1998,"claim":"Confirming the damage-recognition activity of the heterodimer in a genetically defined system, Rad4-Rad23 was shown to bind diverse bulky lesions preferentially and to complement NER-deficient extracts.","evidence":"EMSA and in vitro NER complementation with affinity-purified yeast Rad4-Rad23","pmids":["9837874"],"confidence":"Medium","gaps":["Mechanism of preferential binding not resolved","Did not address chromatin context"]},{"year":2004,"claim":"Addressing how XPC abundance is controlled, RAD23 was found to stabilize Rad4 against proteasomal degradation independently of its proteasome-shuttling function, and the NEF4 ligase was shown to govern Rad4 turnover.","evidence":"Yeast genetics with Rad23 separation-of-function mutants; NEF4/Ubc13 mutant protein-level analysis","pmids":["15601997","15226437"],"confidence":"Medium","gaps":["Degradation control characterized in yeast only","The protective short motif's mechanism not structurally defined"]},{"year":2005,"claim":"Resolving how lesion recognition is relayed and how XPC stability is tuned after damage, UV-DDB-dependent ubiquitylation was shown to transfer recognition to XPC, while SUMO modification protects XPC from degradation.","evidence":"Reconstituted CRL4-DDB2 ubiquitylation, cell-free NER, reciprocal co-IP; western blot with siRNA and NER-deficient cell lines","pmids":["15882621","16030353"],"confidence":"High","gaps":["Did not define the fate of ubiquitylated XPC on chromatin","SUMO study is single-lab Medium confidence"]},{"year":2006,"claim":"Connecting damage recognition to chromatin accessibility, Rad4-Rad23 was shown to interact with SWI/SNF and drive UV-induced nucleosome remodeling required for NER at silent loci.","evidence":"Co-purification, SWI/SNF mutant genetics, restriction-accessibility nucleosome remodeling assay in yeast","pmids":["17013386"],"confidence":"High","gaps":["Generality beyond the HML locus not established","Human XPC-SWI/SNF interaction not demonstrated here"]},{"year":2007,"claim":"Providing the structural foundation for indirect lesion recognition, the Rad4-DNA crystal structure revealed β-hairpin insertion and base-pair flip-out, and footprinting linked the degree of XPC-induced helix opening to NER efficiency.","evidence":"X-ray crystallography of Rad4-CPD-DNA; permanganate footprinting, EMSA and reconstituted NER incision on B[a]P/cisplatin lesions","pmids":["17882165","17525733"],"confidence":"High","gaps":["CPD-linked nucleotides were disordered, leaving lesion-strand interactions unresolved","Did not capture the kinetics of recognition"]},{"year":2008,"claim":"Defining how nuclear XPC availability is regulated, FRAP and fractionation showed XPC shuttles between nucleus and cytoplasm under basal conditions and is retained on chromatin upon damage, and Rad33/Centrin2-type binding was shown to suppress XPC modification.","evidence":"FRAP and live-cell GFP-XPC imaging with fractionation; yeast Rad4-Rad33 interface mutagenesis and repair assays","pmids":["18682493","18387345"],"confidence":"Medium","gaps":["Import/export machinery not identified","Functional consequence of shuttling for repair rate not quantified"]},{"year":2009,"claim":"Extending XPC function beyond DNA, Rad4 was shown to act in proteasomal degradation of ubiquitylated substrates at a post-ubiquitylation step, coordinating with the Rad23-Ufd2 pathway.","evidence":"Yeast deletion analysis, ubiquitylation and substrate degradation assays, cellular fractionation","pmids":["19889839"],"confidence":"Medium","gaps":["Mechanism by which Rad4 promotes substrate delivery to the proteasome unclear","Relevance to mammalian XPC not addressed"]},{"year":2010,"claim":"Identifying a non-NER enzymatic partnership, the XPC complex was shown to stimulate TDG glycosylase turnover by displacing TDG from abasic products, requiring direct physical interaction; deubiquitinase control of Rad4 levels was also defined.","evidence":"In vitro glycosylase assays with binding controls and human-vs-E.coli comparison; yeast Ubp3 co-IP and catalytic-mutant analysis","pmids":["20798892","20876584"],"confidence":"Medium","gaps":["Physiological significance of TDG stimulation not yet shown in cells","Structural basis of XPC-TDG contact unknown"]},{"year":2012,"claim":"Clarifying RAD23's temporal role, live-cell imaging showed RAD23 enables initial XPC loading but dissociates upon lesion binding and does not act downstream.","evidence":"Live-cell fluorescence microscopy with siRNA knockdown and UV damage localization","pmids":["22431748"],"confidence":"Medium","gaps":["Trigger for RAD23 release not defined","Single-lab imaging without structural correlation"]},{"year":2013,"claim":"Linking XPC to tumor-suppressor turnover, XPC was shown to promote MDM2-mediated p53 degradation at a post-ubiquitylation step, with a pathogenic XPC mutant defective for MDM2 binding.","evidence":"Co-IP, protein stability and proteasome-association assays, XPC W690S mutant analysis","pmids":["24258024"],"confidence":"Medium","gaps":["How XPC couples ubiquitylated p53 to the proteasome mechanistically unresolved","In vivo consequence for p53 signaling not established"]},{"year":2014,"claim":"Explaining how XPC is cleared from chromatin, p97/VCP segregase was shown to extract DDB2 and XPC after repair, preventing genome instability from prolonged retention.","evidence":"Chromatin fractionation, p97 siRNA, repair and chromosomal-aberration assays with genetic rescue","pmids":["24770583"],"confidence":"High","gaps":["Ubiquitin signal recognized by p97 on XPC not precisely defined","Timing relative to RNF111 ubiquitylation not resolved"]},{"year":2015,"claim":"These studies established the post-recognition handoff and quality control: RNF111 ubiquitylation releases XPC to load XPG/XPF, TFIIH undergoes lesion-dependent verification, holo-XPC architecture was visualized, and XPC was found to moonlight as a stem-cell coactivator.","evidence":"Live imaging/co-IP/NER assays (RNF111); in vitro TFIIH ATPase/helicase assays; single-particle EM of XPC-RAD23B-CETN2; ChIP-seq and OCT4/SOX2 co-IP","pmids":["26151477","26384665","26627236","25901318"],"confidence":"High","gaps":["How RNF111 and p97 activities are temporally ordered not fully integrated","Coactivator role mechanism (Medium) needs structural detail"]},{"year":2016,"claim":"Resolving the physical mechanism and kinetics of recognition, single-molecule and temperature-jump studies defined the two-step twist-open mechanism and assigned the β-hairpin to stable lesion engagement rather than initial detection or unwinding.","evidence":"Single-molecule fluorescence/AFM with β-hairpin deletion and in vivo UV assays; temperature-jump spectroscopy with mutagenesis","pmids":["27720644","27035942"],"confidence":"High","gaps":["Most kinetic work done on yeast Rad4","How the search transitions to verification not captured"]},{"year":2017,"claim":"Identifying upstream escort and deubiquitylation steps, PARP1 was shown to escort XPC to lesions DDB2-independently, USP11 to deubiquitylate and retain XPC, and the XPC-TDG axis to drive active demethylation supporting reprogramming.","evidence":"Co-IP, live-cell imaging, purified-protein handover (PARP1); deubiquitylation and NER assays (USP11); methylation profiling, TDG turnover, iPSC assays","pmids":["28760956","29228550","28512237"],"confidence":"Medium","gaps":["Relative contributions of PARP1 escort vs UV-DDB recognition not quantified","Demethylation role causality in reprogramming not fully isolated"]},{"year":2018,"claim":"Defining a transcriptional role in undamaged cells, XPC was shown to recruit the KAT2A/ATAC acetyltransferase complex to promoters and promote E2F1 binding, sustaining H3K9 acetylation and pre-initiation complex formation.","evidence":"ChIP-seq, RNA-seq, co-IP of XPC with KAT2A and E2F1, histone modification assays","pmids":["29973595"],"confidence":"Medium","gaps":["Whether this requires XPC's DNA-binding/NER activity unclear","Direct vs indirect recruitment of ATAC not separated"]},{"year":2019,"claim":"Capturing the recognition intermediate at high resolution and the search dynamics, the Rad4-6-4PP structure showed both lesion base pairs flipped with BHD2-initiated bending, while human XPC-RAD23B was shown to hop along DNA and engage CPDs in transient and stable states.","evidence":"X-ray crystallography with 4-µs MD; single-molecule imaging across ionic strengths","pmids":["31106376","31372632"],"confidence":"High","gaps":["Direct visualization of the CPD-resistant conformation limited","Human search-state study is Medium confidence single-lab"]},{"year":2021,"claim":"Revealing the architecture of co-engagement, the cryo-EM Rad4-Rad23-Rad33/TFIIH structure showed DNA straddling Rad4 and the XPB-equivalent subunit with lesion-site unwinding enabling simultaneous binding.","evidence":"Cryo-EM of the yeast NER initiation complex on a carcinogen-DNA adduct","pmids":["34099686"],"confidence":"High","gaps":["Limited resolution (3.9–9.2 Å) for side-chain detail","Yeast complex; XPD lesion-delivery step inferred"]},{"year":2022,"claim":"Connecting XPC to chromatin expansion at hard-to-detect lesions, XPC was shown to constitutively bind PARP1/PARP2, stimulate PAR synthesis, and recruit/activate the remodeler ALC1 to promote CPD repair.","evidence":"MS interactomics, co-IP, PAR synthesis assays, chromatin remodeling assays, epistasis","pmids":["35963869"],"confidence":"High","gaps":["Quantitative contribution of ALC1 remodeling to overall NER not defined","Interplay with SWI/SNF remodeling pathway not addressed"]},{"year":2023,"claim":"Resolving the lesion hand-off step, cryo-EM of human XPC-TFIIH-XPA showed XPA kinking the DNA and shifting XPC and the lesion relative to TFIIH so XPB and XPD oppositely track the strand to position the lesion for XPD verification.","evidence":"Cryo-EM of the human XPC-TFIIH-XPA complex on damaged DNA","pmids":["37076618"],"confidence":"High","gaps":["Transition to dual incision by XPG/XPF not captured","Role of XPC ubiquitylation within this assembly not structurally resolved"]},{"year":null,"claim":"How XPC's many regulatory inputs—sequential CRL4-DDB2/RNF111 ubiquitylation, SUMOylation, USP11 deubiquitylation, p97 extraction, PARP escort, and RAD23/Centrin2/Rad33 binding—are temporally integrated with the structural handoff to TFIIH/XPA, and how the NER and transcriptional/demethylation/p53 functions are partitioned in cells, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified temporal model linking XPC modification states to the structural intermediates","Mechanistic separation of NER vs non-NER roles in vivo not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,10,13,31,32]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,10,12,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,26,27,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[24,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[19,15,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,30,33]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9,22]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[17,25]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,3,4,5,15,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,18,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[24,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4,9,28,29]}],"complexes":["XPC-RAD23B-CETN2 (holo-XPC)","XPC-TFIIH-XPA NER preincision complex","ATAC/KAT2A acetyltransferase complex"],"partners":["RAD23B","CETN2","DDB2","XPA","PARP1","TDG","KAT2A","MDM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01831","full_name":"DNA repair protein complementing XP-C cells","aliases":["Xeroderma pigmentosum group C-complementing protein","p125"],"length_aa":940,"mass_kda":106.0,"function":"Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex (PubMed:10734143, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19609301, PubMed:19941824, PubMed:20028083, PubMed:20649465, PubMed:20798892, PubMed:9734359). Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides (PubMed:10734143, PubMed:19609301, PubMed:20649465). This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity (PubMed:10734143, PubMed:19609301, PubMed:20649465). The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex (PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892, PubMed:9734359). The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs (PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892, PubMed:9734359). The orientation of XPC complex binding appears to be crucial for inducing a productive NER (PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892, PubMed:9734359). XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery (PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892, PubMed:9734359). Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair (PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892, PubMed:9734359). In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts (PubMed:20028083). XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1 (PubMed:20028083) In absence of DNA repair, the XPC complex also acts as a transcription coactivator: XPC interacts with the DNA-binding transcription factor E2F1 at a subset of promoters to recruit KAT2A and histone acetyltransferase complexes (HAT) (PubMed:29973595, PubMed:31527837). KAT2A recruitment specifically promotes acetylation of histone variant H2A.Z.1/H2A.Z, but not H2A.Z.2/H2A.V, thereby promoting expression of target genes (PubMed:31527837)","subcellular_location":"Nucleus; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q01831/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/XPC","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDC7","stoichiometry":10.0},{"gene":"CETN2","stoichiometry":4.0},{"gene":"CDK7","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/XPC","total_profiled":1310},"omim":[{"mim_id":"621363","title":"MAP7 DOMAIN-CONTAINING PROTEIN 1; MAP7D1","url":"https://www.omim.org/entry/621363"},{"mim_id":"613984","title":"FANCD2 GENE; FANCD2","url":"https://www.omim.org/entry/613984"},{"mim_id":"613208","title":"XPC COMPLEX SUBUNIT, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPC","url":"https://www.omim.org/entry/613208"},{"mim_id":"611153","title":"XPA, DNA DAMAGE RECOGNITION AND REPAIR FACTOR; XPA","url":"https://www.omim.org/entry/611153"},{"mim_id":"610850","title":"XPA-BINDING PROTEIN 2; XAB2","url":"https://www.omim.org/entry/610850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/XPC"},"hgnc":{"alias_symbol":["XPCC","RAD4"],"prev_symbol":[]},"alphafold":{"accession":"Q01831","domains":[{"cath_id":"3.90.260.10","chopping":"198-324_526-612","consensus_level":"high","plddt":91.8407,"start":198,"end":612},{"cath_id":"-","chopping":"684-739","consensus_level":"medium","plddt":87.9018,"start":684,"end":739},{"cath_id":"3.30.70.2460","chopping":"758-822","consensus_level":"medium","plddt":90.6522,"start":758,"end":822}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01831","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01831-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01831-F1-predicted_aligned_error_v6.png","plddt_mean":66.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=XPC","jax_strain_url":"https://www.jax.org/strain/search?query=XPC"},"sequence":{"accession":"Q01831","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01831.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01831/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01831"}},"corpus_meta":[{"pmid":"15882621","id":"PMC_15882621","title":"UV-induced 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/26384665","citation_count":134,"is_preprint":false},{"pmid":"17013386","id":"PMC_17013386","title":"Rad4-Rad23 interaction with SWI/SNF links ATP-dependent chromatin remodeling with nucleotide excision repair.","date":"2006","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17013386","citation_count":122,"is_preprint":false},{"pmid":"8702634","id":"PMC_8702634","title":"Overproduction, purification, and characterization of the XPC subunit of the human DNA repair excision nuclease.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702634","citation_count":119,"is_preprint":false},{"pmid":"12949838","id":"PMC_12949838","title":"Critical DNA damage recognition functions of XPC-hHR23B and XPA-RPA in nucleotide excision repair.","date":"2003","source":"Molecular 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out of the double helix; the expelled nucleotides of the undamaged strand are recognized by Rad4 while the CPD-linked nucleotides become disordered, indicating XPC/Rad4 recognizes lesion-induced helix destabilization rather than the lesion chemistry itself.\",\n      \"method\": \"X-ray crystallography of Rad4-DNA complex with CPD lesion\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of Rad4/XPC bound to damaged DNA with direct structural validation of the flipping mechanism\",\n      \"pmids\": [\"17882165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"UV irradiation induces reversible polyubiquitylation of XPC, dependent on functional UV-DDB activity. XPC and UV-DDB interact physically, and both are polyubiquitylated by the recombinant UV-DDB-ubiquitin ligase complex (CRL4-DDB2). Ubiquitylation alters the DNA-binding properties of XPC and UV-DDB and is required for cell-free NER of UV-induced (6-4) photoproducts specifically when UV-DDB is bound to the lesion, supporting a model in which ubiquitylation transfers lesion recognition from UV-DDB to XPC.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant UV-DDB-ubiquitin ligase complex, cell-free NER assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted ubiquitylation in vitro, functional NER assay, reciprocal co-IP, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"15882621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"XPC protein is modified by both SUMO-1 and ubiquitin following UV irradiation in mammalian cells. These modifications require the functions of DDB2 and XPA. Sumoylation of XPC protects it from proteasomal degradation, as XPC is significantly degraded in XP-A cells where sumoylation does not occur.\",\n      \"method\": \"Western blot, reciprocal immunoprecipitation, siRNA knockdown, NER-deficient cell lines, proteasome inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with siRNA validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16030353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"XPC protein forms a tight complex with HHR23B. Both XPC alone and the XPC-HHR23B heterodimer bind DNA with high affinity and prefer UV-damaged DNA. XPC alone (without HHR23B) is sufficient for reconstitution of human excision nuclease activity in vitro; HHR23B has no detectable additional effect on excision activity.\",\n      \"method\": \"Recombinant protein overexpression/purification, in vitro DNA binding assays, reconstituted human excision nuclease assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins demonstrating XPC sufficiency for excision nuclease activity\",\n      \"pmids\": [\"8702634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNF111 (a SUMO-targeted ubiquitin ligase) promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. This ubiquitylation promotes the release of XPC from damaged DNA after NER initiation and is required for stable incorporation of the NER endonucleases XPG and ERCC1/XPF, establishing sequential XPC ubiquitylation by CRL4(DDB2) and RNF111 as a quality-control mechanism for NER progression.\",\n      \"method\": \"Live-cell imaging, siRNA knockdown, immunoprecipitation, ubiquitylation assays, NER repair assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, co-IP, functional NER assay), demonstrated direct mechanistic consequence of ubiquitylation for downstream factor recruitment\",\n      \"pmids\": [\"26151477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tripartite damage verification in NER: XPC initially detects lesions and recruits TFIIH; bulky lesions inhibit the ATPase and helicase activities of XPB and XPD in the TFIIH core (Core7), promoting NER. XPA activates unwinding of normal DNA by Core7 but inhibits Core7 helicase activity in the presence of bulky lesions. The CAK module of TFIIH inhibits DNA binding by TFIIH and enhances XPC-dependent specific recruitment of TFIIH.\",\n      \"method\": \"In vitro ATPase and helicase assays with purified human ten-subunit TFIIH and Core7, defined substrate specificity experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemical assays with purified homogeneous human TFIIH, multiple enzyme activity measurements\",\n      \"pmids\": [\"26384665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The yeast damage-recognition heterodimer Rad4-Rad23 physically interacts with SWI/SNF chromatin-remodeling complex subunits Snf6 and Snf5; this interaction is stimulated by UV irradiation. SWI/SNF is required for efficient NER at the transcriptionally silent HML locus and mediates UV-induced nucleosome rearrangement at that locus, linking XPC/Rad4-mediated damage recognition to ATP-dependent chromatin remodeling.\",\n      \"method\": \"Co-purification of SWI/SNF with Rad4-Rad23, genetic analysis in SWI/SNF mutants, restriction enzyme accessibility assay for nucleosome remodeling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-purification of complex plus functional NER assay in chromatin plus nucleosome remodeling assay, multiple orthogonal methods\",\n      \"pmids\": [\"17013386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RAD23 proteins facilitate damage recognition by XPC but dissociate rapidly from XPC upon XPC binding to UV-induced DNA lesions. In the absence of RAD23, XPC association with UV-induced lesions is impaired. RAD23 does not participate in downstream NER events after damage recognition.\",\n      \"method\": \"Live-cell fluorescence microscopy, siRNA knockdown, UV damage localization assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with siRNA knockdown, single lab, direct visualization of XPC-RAD23 dynamics at damage sites\",\n      \"pmids\": [\"22431748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rad23 stabilizes Rad4 from proteasomal degradation through a specific short amino acid motif. Ubiquitin-conjugating enzymes Ubc4 and Ubc5 and the proteasome regulate Rad4 levels. Rad23's role in stabilizing Rad4 is independent of its role in proteasome interaction (via UbL domain), as demonstrated by complementation with separation-of-function mutants.\",\n      \"method\": \"Genetic analysis, protein stability assays, complementation with Rad23 separation-of-function mutants in yeast\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with separation-of-function mutants, single lab, well-controlled yeast genetics\",\n      \"pmids\": [\"15601997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The p97/VCP/Cdc48 segregase complex is required for timely extraction of DDB2 and XPC from chromatin after UV damage. Prolonged retention of DDB2 and XPC in chromatin due to loss of p97 impairs DNA excision repair and leads to chromosomal aberrations. Concomitant downregulation of DDB2 or XPC rescues genome instability in p97-deficient cells.\",\n      \"method\": \"Chromatin fractionation, siRNA knockdown of p97, UV-lesion repair assays, chromosomal aberration analysis, epistasis experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, repair assays, genetic rescue), direct mechanistic link between p97-mediated extraction and XPC function\",\n      \"pmids\": [\"24770583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Rad4 (yeast XPC) tethered to undamaged DNA (via disulfide crosslink) shows that Rad4 can flip out normal nucleotides and adopts a conformation similar to that seen with damaged DNA. Temperature-jump perturbation spectroscopy reveals kinetics of lesion opening. Results support a kinetic gating mechanism for damage recognition whereby lesion selectivity arises from kinetic competition between DNA opening and Rad4's residence time per site.\",\n      \"method\": \"X-ray crystallography of disulfide-tethered Rad4-DNA complex on undamaged DNA, temperature-jump perturbation spectroscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biophysical kinetic measurements, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25562780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Single-molecule fluorescence microscopy of quantum dot-labeled Rad4-Rad23 (yeast XPC-RAD23B) shows three types of 1D motion on DNA: non-motile, random diffusion, and constrained. Deletion of BHD3's β-hairpin tip increases constrained motion at the expense of stable lesion binding, without abolishing damage-specific binding or cellular UV resistance, indicating this motif is needed for stable lesion engagement but not for initial damage detection.\",\n      \"method\": \"Single-molecule fluorescence microscopy, quantum dot labeling, atomic force microscopy, in vivo UV resistance assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — single-molecule imaging plus AFM plus in vivo genetic validation, multiple orthogonal methods\",\n      \"pmids\": [\"27720644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Temperature-jump spectroscopy reveals a two-step 'twist-open' mechanism for Rad4/XPC lesion recognition: an early ~100–500 μs step corresponding to nonspecific DNA unwinding/twisting, followed by a ~10 ms rate-limiting step of nucleotide flipping/opening. The β-hairpin is not required for DNA unwinding but is essential for full nucleotide flipping.\",\n      \"method\": \"Temperature-jump perturbation spectroscopy with fluorescence detection, mutagenesis of β-hairpin domain\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biophysical reconstitution with mutagenesis, directly captures kinetics of the recognition mechanism\",\n      \"pmids\": [\"27035942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of Rad4-Rad23 (yeast XPC-Rad23B) bound to 6-4PP-containing DNA shows that Rad4 flips out both nucleotide pairs containing the 6-4PP, forming an 'open' conformation. Molecular dynamics simulations show Rad4 initiates engagement via BHD2 bending/untwisting from the minor groove, with stepwise extrusion of the base pairs. CPD resists such Rad4-induced distortions, explaining the differential repair efficiency.\",\n      \"method\": \"X-ray crystallography, molecular dynamics simulations (4 μs)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of Rad4/XPC with physiological substrate complemented by extensive MD simulations\",\n      \"pmids\": [\"31106376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human XPC-RAD23B diffuses along DNA via hopping (ionic-strength-dependent), allowing bypass of protein obstacles during lesion search. XPC-RAD23B makes futile attempts to bind CPDs, and binds CPDs in two states: stable (lesion recognition) and transient (interrogation), consistent with low CPD recognition efficiency.\",\n      \"method\": \"Single-molecule fluorescence imaging on tethered DNA, analysis of diffusion coefficients vs. ionic strength\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-molecule imaging of human XPC-RAD23B, single lab, direct mechanistic characterization of search dynamics\",\n      \"pmids\": [\"31372632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of human XPC-TFIIH-XPA on damaged DNA reveal the mechanism of lesion hand-off: XPA binds between XPB and XPD, kinks the DNA duplex, and shifts XPC and the DNA lesion by nearly a helical turn relative to TFIIH Core7, positioning the lesion outside Core7. XPB and XPD, tracking the lesion-containing strand in opposite directions, push and pull the lesion strand into XPD for verification.\",\n      \"method\": \"Cryo-EM structural determination of human XPC-TFIIH-XPA complex on damaged DNA\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures directly capturing multiple intermediates of lesion handoff from XPC to TFIIH/XPA\",\n      \"pmids\": [\"37076618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of TFIIH/Rad4-Rad23-Rad33 on a carcinogen-DNA adduct lesion (3.9–9.2 Å resolution) shows ~30 bp DNA straddling between Rad4 and the Ssl2 (XPB) subunit of TFIIH, with DNA unwinding at the lesion site. Simultaneous binding of Rad4 and TFIIH is enabled by unwinding at the lesion. Ssl2 translocation coupled with torque would extend DNA unwinding and deliver the damaged strand to Rad3 (XPD) in an open form for lesion scanning.\",\n      \"method\": \"Cryo-EM structure determination of Rad4-Rad23-Rad33/TFIIH complex on DNA\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure of the NER initiation complex directly revealing the architecture of Rad4/XPC-TFIIH co-engagement on damaged DNA\",\n      \"pmids\": [\"34099686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PARP1 forms a stable complex with XPC in the nucleoplasm under steady-state conditions and directly escorts XPC to UV-induced DNA lesions after irradiation in a DDB2-independent manner. PARP1 catalytic activity is not required for initial XPC complex formation but enhances XPC recruitment to lesion sites. Purified PARP1-XPC complex facilitates handover of XPC to the UV-lesion site in the presence of the UV-DDB ligase complex.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, in vitro pull-down with purified proteins, UV irradiation experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and purified protein reconstitution, single lab, multiple supporting experiments\",\n      \"pmids\": [\"28760956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP1 and PARP2 are constitutive interactors of XPC. XPC stimulates PARP1 synthesis of poly-(ADP-ribose) (PAR) at UV lesions, enabling recruitment and activation of the chromatin remodeler ALC1. PARP2 modulates ALC1 retention at damage sites. ALC1 mediates chromatin expansion at UV-induced lesions, promoting timely repair of CPDs.\",\n      \"method\": \"Mass spectrometry interactomics, Co-IP, live-cell imaging, PAR synthesis assays, chromatin remodeling assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-identified interaction confirmed by Co-IP, functional PAR synthesis assay, chromatin remodeling assay, mechanistic epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"35963869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast Rad4 protein physically interacts with TFIIH (factor b) in vitro, suggesting Rad4/XPC directly recruits TFIIH as part of NER repairosome assembly.\",\n      \"method\": \"In vitro binding assay of Rad4 with purified TFIIH (factor b) subunits\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding with purified TFIIH, early foundational experiment, single lab\",\n      \"pmids\": [\"8196602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NEF4 (containing Rad7, Rad16 ATPase, and Elc1) regulates Rad4 protein levels; mutations in NEF4 or the E2 enzyme Ubc13 result in elevated Rad4 levels and increased ubiquitylated Rad23 species, establishing that NEF4 controls Rad4 turnover through a ubiquitin ligase mechanism.\",\n      \"method\": \"Genetic mutant analysis in yeast, protein level measurements, ubiquitylation detection by Western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with direct protein-level measurements, single lab\",\n      \"pmids\": [\"15226437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast deubiquitinase Ubp3 physically interacts with Rad4 and the 26S proteasome (both in vivo and in vitro) and facilitates Rad4 degradation. Disruption of UBP3 increases UV resistance and Rad4 levels, especially in rad23Δ cells. Catalytically inactive Ubp3-C469A cannot affect NER or Rad4 levels.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro, yeast genetic analysis, UV sensitivity assays, protein stability measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus active site mutant confirmation plus genetic analysis, single lab\",\n      \"pmids\": [\"20876584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GFP-tagged XPC continuously associates with and dissociates from chromatin in undamaged cells. UV damage retards XPC mobility (shown by FRAP). XPC undergoes continuous nuclear export and import under basal conditions, which is blocked when NER lesions are present. This nucleus-cytoplasm shuttling controls steady-state nuclear XPC levels and allows concentration increases under genotoxic stress.\",\n      \"method\": \"FRAP (fluorescence recovery after photobleaching), live-cell imaging of GFP-XPC, nuclear-cytoplasmic fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell FRAP and imaging directly demonstrating shuttling and damage-dependent retention, single lab\",\n      \"pmids\": [\"18682493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Rad33 directly binds Rad4 via the same conserved amino acids required for the interaction of human XPC with Centrin2. The Rad4-Rad33 interaction prevents UV-induced Rad4 modification; disruption of this interaction enhances Rad4 modification (dependent on TCR factor Rad26) and causes a repair defect.\",\n      \"method\": \"Direct binding assays, mutational analysis of Rad4-Rad33 interaction interface, yeast genetic analysis, UV repair assays\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by mutagenesis, genetic rescue experiments, single lab\",\n      \"pmids\": [\"18387345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The XPC-RAD23B-CETN2 complex functions as a stem cell coactivator (SCC) required for OCT4/SOX2 transcriptional activation in embryonic stem cells. XPC is identified as the subunit essential for interaction with OCT4 and SOX2, and SCC binds regulatory regions of pluripotency genes. OCT4 and SOX2 are the primary transcription factors recruiting SCC to these promoters.\",\n      \"method\": \"Genome-wide ChIP-seq mapping of RAD23B, transcriptional profiling of SCC-depleted ESCs, co-immunoprecipitation of XPC with OCT4/SOX2\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus Co-IP with defined subunit requirement, single lab, two orthogonal approaches\",\n      \"pmids\": [\"25901318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In undamaged cells, XPC co-localizes with RNA Pol II and active histone modification marks at a subset of class II promoters. XPC depletion reduces H3K9 acetylation and pre-initiation complex formation at target genes. XPC physically interacts with the histone acetyltransferase KAT2A and recruits the KAT2A-containing ATAC complex to promoters. XPC also interacts with E2F1 and promotes E2F1 binding to its DNA element at target promoters.\",\n      \"method\": \"ChIP-seq, RNA-seq, co-immunoprecipitation of XPC with KAT2A and E2F1, histone modification assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus Co-IP confirming XPC-KAT2A and XPC-E2F1 interactions, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29973595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"XPC DNA repair complex cooperates with TDG genome-wide to stimulate turnover of TDG-abasic site intermediates during active DNA demethylation, overcoming slow TDG product dissociation. XPC-induced DNA demethylation in somatic cells facilitates cellular reprogramming and generation of more robust iPSCs.\",\n      \"method\": \"Genome-wide methylation analysis, biochemical TDG turnover assays, iPSC reprogramming experiments, Co-IP\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical TDG activity assay plus genome-wide methylation profiling, single lab\",\n      \"pmids\": [\"28512237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"XPC complex stimulates the enzymatic turnover of TDG (thymine DNA glycosylase) by promoting TDG displacement from its abasic-site product, and also stimulates sumoylated TDG and SMUG1 activities. XPC effects on E. coli TDG homolog (EcMUG) are only marginal; EcMUG does not significantly interact with XPC. Physical interaction between XPC and the glycosylase is required for stimulation of glycosylase activity.\",\n      \"method\": \"In vitro glycosylase activity assays, protein-protein interaction assays, comparison of XPC effects on human vs. E. coli TDG homologs\",\n      \"journal\": \"Journal of nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assays with direct binding controls, single lab\",\n      \"pmids\": [\"20798892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"XPC participates in MDM2-mediated p53 degradation via direct interaction with MDM2. p53 remains ubiquitylated in XPC-deficient cells but its association with the proteasome is drastically reduced, indicating XPC regulates a postubiquitylation step. The pathogenic XPC W690S mutant is specifically defective for MDM2 binding and p53 degradation. XPC overexpression renders p53 unstable even after UV irradiation.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, XPC mutant analysis, proteasome association assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus pathogenic mutant analysis plus functional proteasome association assay, single lab\",\n      \"pmids\": [\"24258024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP11 deubiquitylates XPC and promotes its retention at DNA damage sites. UV irradiation induces USP11 recruitment to chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner. USP11 positively regulates NER capacity.\",\n      \"method\": \"Co-immunoprecipitation, chromatin fractionation, deubiquitylation assays, NER activity assays, UV irradiation experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deubiquitylation assay plus functional NER measurement, single lab\",\n      \"pmids\": [\"29228550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rad4 (yeast XPC) regulates proteasomal degradation of ubiquitylated substrates at a postubiquitylation step. Rad4 and Rad23 share common substrates; substrates in rad4Δ cells remain ubiquitylated. Rad4 participates in the Rad23-Ufd2 proteolytic pathway. Upon DNA damage, Rad4 concentrates in the nucleus and degradation of non-nuclear substrate Pex29 is compromised, suggesting coordination between DNA repair and proteolysis.\",\n      \"method\": \"Yeast genetic deletion analysis, ubiquitylation assays, substrate degradation assays, cellular fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with direct protein degradation measurements, single lab\",\n      \"pmids\": [\"19889839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human XPC-HR23B exhibits lesion-specific patterns of DNA helix opening (detected by permanganate footprinting) that differ among three stereoisomeric B[a]P-N2-dG lesions and differ from cisplatin adducts. The extent of helix distortion and overall XPC/HR23B binding to double-stranded DNA containing these lesions correlates with dual incisions by reconstituted NER.\",\n      \"method\": \"Permanganate footprinting assay, electrophoretic mobility shift assay (EMSA), reconstituted NER incision assay with six purified factors\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted NER incision assay with purified factors plus footprinting, single lab\",\n      \"pmids\": [\"17525733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The yeast Rad4-Rad23 complex binds preferentially to UV-irradiated and AAF-treated damaged DNA over undamaged DNA, as demonstrated by gel mobility shift assays. The complex complements in vitro NER defects of rad4 and rad23 mutant extracts.\",\n      \"method\": \"Affinity-purified epitope-tagged Rad4-Rad23, EMSA, in vitro NER complementation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding preference demonstrated with complementation validation, single lab\",\n      \"pmids\": [\"9837874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The majority of HHR23B exists in a free, non-complexed form, while a minor fraction is tightly associated with XPC. HHR23A is not detected in complex with XPC. Immunofluorescence studies show XPC, HHR23B, and HHR23A all reside in the nucleus.\",\n      \"method\": \"Heparin chromatography, gel filtration, native gel electrophoresis, immunodepletion, immunofluorescence\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical fractionation methods and immunolocalization, single lab\",\n      \"pmids\": [\"8692695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Single-particle electron microscopy of the human holo-XPC complex (XPC-RAD23B-CETN2) reveals a flexible, ear-shaped structure that undergoes localized loss of order upon DNA binding. The yeast Rad4 holo-complex has similar overall architecture. Subunit positions were mapped by tagging and deletion experiments.\",\n      \"method\": \"Single-particle electron microscopy, subunit tagging and deletion mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EM structure with biochemical subunit mapping, single lab\",\n      \"pmids\": [\"26627236\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XPC (yeast ortholog Rad4) is the primary damage sensor for global genome NER: it interrogates DNA via a stepwise 'twist-open' kinetic gating mechanism, inserting a β-hairpin to flip out two destabilized base pairs (recognizing the undamaged strand opposite the lesion), then recruits TFIIH and XPA for tripartite damage verification with lesion hand-off coordinated by XPA-induced DNA kinking; XPC is regulated by sequential ubiquitylation (CRL4-DDB2, then RNF111/SUMO) that controls its release from damaged DNA to permit downstream factor assembly, by RAD23-mediated stabilization from proteasomal degradation, by PARP1-mediated escort to lesions, and by p97-dependent chromatin extraction; beyond NER, XPC stimulates TDG glycosylase activity and TDG-mediated DNA demethylation, participates in MDM2-mediated p53 proteolysis, recruits the ATAC/KAT2A acetyltransferase complex to promoters via interaction with E2F1, and engages PARP1/2 to recruit the chromatin remodeler ALC1 for repair of difficult-to-detect lesions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"XPC is the primary damage sensor for global-genome nucleotide excision repair (NER), recognizing lesions indirectly through the helix destabilization they impose rather than through lesion chemistry itself [#0, #3]. Structural and biophysical work establishes that XPC (and its yeast ortholog Rad4) interrogates DNA by a two-step 'twist-open' mechanism\\u2014a fast nonspecific unwinding/untwisting step followed by a rate-limiting nucleotide-flipping step in which a \\u03b2-hairpin is inserted through the duplex to expel two destabilized base pairs and engage the undamaged strand opposite the lesion [#0, #12, #13]; lesion selectivity arises from kinetic gating, the competition between the rate of DNA opening and XPC's residence time at each site, which explains why readily distorted 6-4 photoproducts are recognized far more efficiently than rigid CPDs [#10, #13, #14]. XPC functions as a heterodimer with HHR23B/RAD23, which facilitates damage recognition and protects XPC from proteasomal degradation but dissociates upon stable lesion engagement and plays no role in downstream NER [#3, #7, #8]. Once bound, XPC directly recruits TFIIH and hands the lesion off for tripartite verification: XPA binds between XPB and XPD, kinks the duplex, and shifts XPC and the lesion relative to the TFIIH core so that XPB and XPD track the damaged strand in opposite directions and feed it into XPD for scanning [#15, #16, #19, #5]. XPC engagement and turnover are controlled by sequential ubiquitylation\\u2014by CRL4(DDB2), which transfers lesion recognition from UV-DDB to XPC, and then by the SUMO-targeted ligase RNF111, whose K63-linked ubiquitylation releases XPC from damaged DNA to permit stable loading of the XPG and ERCC1/XPF endonucleases\\u2014together with p97/VCP-mediated chromatin extraction, deubiquitylation by USP11, and SUMO-mediated stabilization [#1, #2, #4, #9, #29]. XPC also couples lesion recognition to chromatin remodeling, recruiting SWI/SNF and, via PARP1/PARP2-dependent PAR synthesis, the remodeler ALC1 to expand chromatin at difficult-to-detect lesions [#6, #17, #18]. Beyond NER, XPC moonlights in transcription and genome maintenance: as part of an XPC-RAD23B-CETN2 stem-cell coactivator it supports OCT4/SOX2-driven pluripotency gene expression [#24], it recruits the KAT2A/ATAC acetyltransferase complex to promoters through E2F1 [#25], it stimulates TDG glycosylase turnover during active DNA demethylation [#26, #27], and it promotes MDM2-mediated proteasomal degradation of p53 at a post-ubiquitylation step [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing how the NER initiator connects to downstream machinery, Rad4/XPC was shown to physically contact TFIIH, defining it as the factor that nucleates repairosome assembly.\",\n      \"evidence\": \"In vitro binding of yeast Rad4 with purified TFIIH (factor b)\",\n      \"pmids\": [\"8196602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the structural basis or stoichiometry of the Rad4-TFIIH contact\", \"Interaction shown in yeast, not yet for human XPC\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defining XPC's composition and biochemical sufficiency, XPC was shown to form a tight heterodimer with HHR23B, bind preferentially to UV-damaged DNA, and be sufficient alone to reconstitute excision activity.\",\n      \"evidence\": \"Recombinant protein purification, in vitro DNA-binding and reconstituted human excision nuclease assays; biochemical fractionation/immunolocalization\",\n      \"pmids\": [\"8702634\", \"8692695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how XPC discriminates damaged from undamaged DNA at atomic resolution\", \"Functional role of HHR23B not clarified by the excision assay\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Confirming the damage-recognition activity of the heterodimer in a genetically defined system, Rad4-Rad23 was shown to bind diverse bulky lesions preferentially and to complement NER-deficient extracts.\",\n      \"evidence\": \"EMSA and in vitro NER complementation with affinity-purified yeast Rad4-Rad23\",\n      \"pmids\": [\"9837874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of preferential binding not resolved\", \"Did not address chromatin context\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Addressing how XPC abundance is controlled, RAD23 was found to stabilize Rad4 against proteasomal degradation independently of its proteasome-shuttling function, and the NEF4 ligase was shown to govern Rad4 turnover.\",\n      \"evidence\": \"Yeast genetics with Rad23 separation-of-function mutants; NEF4/Ubc13 mutant protein-level analysis\",\n      \"pmids\": [\"15601997\", \"15226437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation control characterized in yeast only\", \"The protective short motif's mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolving how lesion recognition is relayed and how XPC stability is tuned after damage, UV-DDB-dependent ubiquitylation was shown to transfer recognition to XPC, while SUMO modification protects XPC from degradation.\",\n      \"evidence\": \"Reconstituted CRL4-DDB2 ubiquitylation, cell-free NER, reciprocal co-IP; western blot with siRNA and NER-deficient cell lines\",\n      \"pmids\": [\"15882621\", \"16030353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the fate of ubiquitylated XPC on chromatin\", \"SUMO study is single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connecting damage recognition to chromatin accessibility, Rad4-Rad23 was shown to interact with SWI/SNF and drive UV-induced nucleosome remodeling required for NER at silent loci.\",\n      \"evidence\": \"Co-purification, SWI/SNF mutant genetics, restriction-accessibility nucleosome remodeling assay in yeast\",\n      \"pmids\": [\"17013386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality beyond the HML locus not established\", \"Human XPC-SWI/SNF interaction not demonstrated here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Providing the structural foundation for indirect lesion recognition, the Rad4-DNA crystal structure revealed \\u03b2-hairpin insertion and base-pair flip-out, and footprinting linked the degree of XPC-induced helix opening to NER efficiency.\",\n      \"evidence\": \"X-ray crystallography of Rad4-CPD-DNA; permanganate footprinting, EMSA and reconstituted NER incision on B[a]P/cisplatin lesions\",\n      \"pmids\": [\"17882165\", \"17525733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CPD-linked nucleotides were disordered, leaving lesion-strand interactions unresolved\", \"Did not capture the kinetics of recognition\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defining how nuclear XPC availability is regulated, FRAP and fractionation showed XPC shuttles between nucleus and cytoplasm under basal conditions and is retained on chromatin upon damage, and Rad33/Centrin2-type binding was shown to suppress XPC modification.\",\n      \"evidence\": \"FRAP and live-cell GFP-XPC imaging with fractionation; yeast Rad4-Rad33 interface mutagenesis and repair assays\",\n      \"pmids\": [\"18682493\", \"18387345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Import/export machinery not identified\", \"Functional consequence of shuttling for repair rate not quantified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extending XPC function beyond DNA, Rad4 was shown to act in proteasomal degradation of ubiquitylated substrates at a post-ubiquitylation step, coordinating with the Rad23-Ufd2 pathway.\",\n      \"evidence\": \"Yeast deletion analysis, ubiquitylation and substrate degradation assays, cellular fractionation\",\n      \"pmids\": [\"19889839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Rad4 promotes substrate delivery to the proteasome unclear\", \"Relevance to mammalian XPC not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying a non-NER enzymatic partnership, the XPC complex was shown to stimulate TDG glycosylase turnover by displacing TDG from abasic products, requiring direct physical interaction; deubiquitinase control of Rad4 levels was also defined.\",\n      \"evidence\": \"In vitro glycosylase assays with binding controls and human-vs-E.coli comparison; yeast Ubp3 co-IP and catalytic-mutant analysis\",\n      \"pmids\": [\"20798892\", \"20876584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of TDG stimulation not yet shown in cells\", \"Structural basis of XPC-TDG contact unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Clarifying RAD23's temporal role, live-cell imaging showed RAD23 enables initial XPC loading but dissociates upon lesion binding and does not act downstream.\",\n      \"evidence\": \"Live-cell fluorescence microscopy with siRNA knockdown and UV damage localization\",\n      \"pmids\": [\"22431748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for RAD23 release not defined\", \"Single-lab imaging without structural correlation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking XPC to tumor-suppressor turnover, XPC was shown to promote MDM2-mediated p53 degradation at a post-ubiquitylation step, with a pathogenic XPC mutant defective for MDM2 binding.\",\n      \"evidence\": \"Co-IP, protein stability and proteasome-association assays, XPC W690S mutant analysis\",\n      \"pmids\": [\"24258024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How XPC couples ubiquitylated p53 to the proteasome mechanistically unresolved\", \"In vivo consequence for p53 signaling not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Explaining how XPC is cleared from chromatin, p97/VCP segregase was shown to extract DDB2 and XPC after repair, preventing genome instability from prolonged retention.\",\n      \"evidence\": \"Chromatin fractionation, p97 siRNA, repair and chromosomal-aberration assays with genetic rescue\",\n      \"pmids\": [\"24770583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin signal recognized by p97 on XPC not precisely defined\", \"Timing relative to RNF111 ubiquitylation not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"These studies established the post-recognition handoff and quality control: RNF111 ubiquitylation releases XPC to load XPG/XPF, TFIIH undergoes lesion-dependent verification, holo-XPC architecture was visualized, and XPC was found to moonlight as a stem-cell coactivator.\",\n      \"evidence\": \"Live imaging/co-IP/NER assays (RNF111); in vitro TFIIH ATPase/helicase assays; single-particle EM of XPC-RAD23B-CETN2; ChIP-seq and OCT4/SOX2 co-IP\",\n      \"pmids\": [\"26151477\", \"26384665\", \"26627236\", \"25901318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RNF111 and p97 activities are temporally ordered not fully integrated\", \"Coactivator role mechanism (Medium) needs structural detail\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolving the physical mechanism and kinetics of recognition, single-molecule and temperature-jump studies defined the two-step twist-open mechanism and assigned the \\u03b2-hairpin to stable lesion engagement rather than initial detection or unwinding.\",\n      \"evidence\": \"Single-molecule fluorescence/AFM with \\u03b2-hairpin deletion and in vivo UV assays; temperature-jump spectroscopy with mutagenesis\",\n      \"pmids\": [\"27720644\", \"27035942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Most kinetic work done on yeast Rad4\", \"How the search transitions to verification not captured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying upstream escort and deubiquitylation steps, PARP1 was shown to escort XPC to lesions DDB2-independently, USP11 to deubiquitylate and retain XPC, and the XPC-TDG axis to drive active demethylation supporting reprogramming.\",\n      \"evidence\": \"Co-IP, live-cell imaging, purified-protein handover (PARP1); deubiquitylation and NER assays (USP11); methylation profiling, TDG turnover, iPSC assays\",\n      \"pmids\": [\"28760956\", \"29228550\", \"28512237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of PARP1 escort vs UV-DDB recognition not quantified\", \"Demethylation role causality in reprogramming not fully isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining a transcriptional role in undamaged cells, XPC was shown to recruit the KAT2A/ATAC acetyltransferase complex to promoters and promote E2F1 binding, sustaining H3K9 acetylation and pre-initiation complex formation.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, co-IP of XPC with KAT2A and E2F1, histone modification assays\",\n      \"pmids\": [\"29973595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this requires XPC's DNA-binding/NER activity unclear\", \"Direct vs indirect recruitment of ATAC not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Capturing the recognition intermediate at high resolution and the search dynamics, the Rad4-6-4PP structure showed both lesion base pairs flipped with BHD2-initiated bending, while human XPC-RAD23B was shown to hop along DNA and engage CPDs in transient and stable states.\",\n      \"evidence\": \"X-ray crystallography with 4-\\u00b5s MD; single-molecule imaging across ionic strengths\",\n      \"pmids\": [\"31106376\", \"31372632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct visualization of the CPD-resistant conformation limited\", \"Human search-state study is Medium confidence single-lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealing the architecture of co-engagement, the cryo-EM Rad4-Rad23-Rad33/TFIIH structure showed DNA straddling Rad4 and the XPB-equivalent subunit with lesion-site unwinding enabling simultaneous binding.\",\n      \"evidence\": \"Cryo-EM of the yeast NER initiation complex on a carcinogen-DNA adduct\",\n      \"pmids\": [\"34099686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Limited resolution (3.9\\u20139.2 \\u00c5) for side-chain detail\", \"Yeast complex; XPD lesion-delivery step inferred\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connecting XPC to chromatin expansion at hard-to-detect lesions, XPC was shown to constitutively bind PARP1/PARP2, stimulate PAR synthesis, and recruit/activate the remodeler ALC1 to promote CPD repair.\",\n      \"evidence\": \"MS interactomics, co-IP, PAR synthesis assays, chromatin remodeling assays, epistasis\",\n      \"pmids\": [\"35963869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of ALC1 remodeling to overall NER not defined\", \"Interplay with SWI/SNF remodeling pathway not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolving the lesion hand-off step, cryo-EM of human XPC-TFIIH-XPA showed XPA kinking the DNA and shifting XPC and the lesion relative to TFIIH so XPB and XPD oppositely track the strand to position the lesion for XPD verification.\",\n      \"evidence\": \"Cryo-EM of the human XPC-TFIIH-XPA complex on damaged DNA\",\n      \"pmids\": [\"37076618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transition to dual incision by XPG/XPF not captured\", \"Role of XPC ubiquitylation within this assembly not structurally resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How XPC's many regulatory inputs\\u2014sequential CRL4-DDB2/RNF111 ubiquitylation, SUMOylation, USP11 deubiquitylation, p97 extraction, PARP escort, and RAD23/Centrin2/Rad33 binding\\u2014are temporally integrated with the structural handoff to TFIIH/XPA, and how the NER and transcriptional/demethylation/p53 functions are partitioned in cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified temporal model linking XPC modification states to the structural intermediates\", \"Mechanistic separation of NER vs non-NER roles in vivo not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 10, 13, 31, 32]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 10, 12, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 26, 27, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [24, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [19, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 30, 33]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9, 22]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [17, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 15, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 18, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [24, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4, 9, 28, 29]}\n    ],\n    \"complexes\": [\n      \"XPC-RAD23B-CETN2 (holo-XPC)\",\n      \"XPC-TFIIH-XPA NER preincision complex\",\n      \"ATAC/KAT2A acetyltransferase complex\"\n    ],\n    \"partners\": [\n      \"RAD23B\",\n      \"CETN2\",\n      \"DDB2\",\n      \"XPA\",\n      \"PARP1\",\n      \"TDG\",\n      \"KAT2A\",\n      \"MDM2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}