Affinage

XPC

DNA repair protein complementing XP-C cells · UniProt Q01831

Length
940 aa
Mass
106.0 kDa
Annotated
2026-06-11
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 Medium

    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)

    PMID:8196602

    Open questions at the time
    • Did not define the structural basis or stoichiometry of the Rad4-TFIIH contact
    • Interaction shown in yeast, not yet for human XPC
  2. 1996 High

    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

    PMID:8692695 PMID:8702634

    Open questions at the time
    • Did not explain how XPC discriminates damaged from undamaged DNA at atomic resolution
    • Functional role of HHR23B not clarified by the excision assay
  3. 1998 Medium

    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

    PMID:9837874

    Open questions at the time
    • Mechanism of preferential binding not resolved
    • Did not address chromatin context
  4. 2004 Medium

    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

    PMID:15226437 PMID:15601997

    Open questions at the time
    • Degradation control characterized in yeast only
    • The protective short motif's mechanism not structurally defined
  5. 2005 High

    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

    PMID:15882621 PMID:16030353

    Open questions at the time
    • Did not define the fate of ubiquitylated XPC on chromatin
    • SUMO study is single-lab Medium confidence
  6. 2006 High

    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

    PMID:17013386

    Open questions at the time
    • Generality beyond the HML locus not established
    • Human XPC-SWI/SNF interaction not demonstrated here
  7. 2007 High

    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

    PMID:17525733 PMID:17882165

    Open questions at the time
    • CPD-linked nucleotides were disordered, leaving lesion-strand interactions unresolved
    • Did not capture the kinetics of recognition
  8. 2008 Medium

    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

    PMID:18387345 PMID:18682493

    Open questions at the time
    • Import/export machinery not identified
    • Functional consequence of shuttling for repair rate not quantified
  9. 2009 Medium

    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

    PMID:19889839

    Open questions at the time
    • Mechanism by which Rad4 promotes substrate delivery to the proteasome unclear
    • Relevance to mammalian XPC not addressed
  10. 2010 Medium

    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

    PMID:20798892 PMID:20876584

    Open questions at the time
    • Physiological significance of TDG stimulation not yet shown in cells
    • Structural basis of XPC-TDG contact unknown
  11. 2012 Medium

    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

    PMID:22431748

    Open questions at the time
    • Trigger for RAD23 release not defined
    • Single-lab imaging without structural correlation
  12. 2013 Medium

    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

    PMID:24258024

    Open questions at the time
    • How XPC couples ubiquitylated p53 to the proteasome mechanistically unresolved
    • In vivo consequence for p53 signaling not established
  13. 2014 High

    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

    PMID:24770583

    Open questions at the time
    • Ubiquitin signal recognized by p97 on XPC not precisely defined
    • Timing relative to RNF111 ubiquitylation not resolved
  14. 2015 High

    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

    PMID:25901318 PMID:26151477 PMID:26384665 PMID:26627236

    Open questions at the time
    • How RNF111 and p97 activities are temporally ordered not fully integrated
    • Coactivator role mechanism (Medium) needs structural detail
  15. 2016 High

    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

    PMID:27035942 PMID:27720644

    Open questions at the time
    • Most kinetic work done on yeast Rad4
    • How the search transitions to verification not captured
  16. 2017 Medium

    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

    PMID:28512237 PMID:28760956 PMID:29228550

    Open questions at the time
    • Relative contributions of PARP1 escort vs UV-DDB recognition not quantified
    • Demethylation role causality in reprogramming not fully isolated
  17. 2018 Medium

    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

    PMID:29973595

    Open questions at the time
    • Whether this requires XPC's DNA-binding/NER activity unclear
    • Direct vs indirect recruitment of ATAC not separated
  18. 2019 High

    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

    PMID:31106376 PMID:31372632

    Open questions at the time
    • Direct visualization of the CPD-resistant conformation limited
    • Human search-state study is Medium confidence single-lab
  19. 2021 High

    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

    PMID:34099686

    Open questions at the time
    • Limited resolution (3.9–9.2 Å) for side-chain detail
    • Yeast complex; XPD lesion-delivery step inferred
  20. 2022 High

    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

    PMID:35963869

    Open questions at the time
    • Quantitative contribution of ALC1 remodeling to overall NER not defined
    • Interplay with SWI/SNF remodeling pathway not addressed
  21. 2023 High

    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

    PMID:37076618

    Open questions at the time
    • Transition to dual incision by XPG/XPF not captured
    • Role of XPC ubiquitylation within this assembly not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 4 GO:0140299 molecular sensor activity 4 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005694 chromosome 2
Pathway
R-HSA-73894 DNA Repair 7 R-HSA-392499 Metabolism of proteins 5 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
CETN2DDB2KAT2AMDM2PARP1RAD23BTDGXPA
Complex memberships
ATAC/KAT2A acetyltransferase complexXPC-RAD23B-CETN2 (holo-XPC)XPC-TFIIH-XPA NER preincision complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. X-ray crystallography of Rad4-DNA complex with CPD lesion Nature High 17882165
2005 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. Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant UV-DDB-ubiquitin ligase complex, cell-free NER assay Cell High 15882621
2005 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. Western blot, reciprocal immunoprecipitation, siRNA knockdown, NER-deficient cell lines, proteasome inhibitor treatment Nucleic acids research Medium 16030353
1996 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. Recombinant protein overexpression/purification, in vitro DNA binding assays, reconstituted human excision nuclease assay The Journal of biological chemistry High 8702634
2015 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. Live-cell imaging, siRNA knockdown, immunoprecipitation, ubiquitylation assays, NER repair assays Nature communications High 26151477
2015 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. In vitro ATPase and helicase assays with purified human ten-subunit TFIIH and Core7, defined substrate specificity experiments Molecular cell High 26384665
2006 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. Co-purification of SWI/SNF with Rad4-Rad23, genetic analysis in SWI/SNF mutants, restriction enzyme accessibility assay for nucleosome remodeling Nature structural & molecular biology High 17013386
2012 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. Live-cell fluorescence microscopy, siRNA knockdown, UV damage localization assays The Journal of cell biology Medium 22431748
2004 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. Genetic analysis, protein stability assays, complementation with Rad23 separation-of-function mutants in yeast Nucleic acids research Medium 15601997
2014 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. Chromatin fractionation, siRNA knockdown of p97, UV-lesion repair assays, chromosomal aberration analysis, epistasis experiments Nature communications High 24770583
2015 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. X-ray crystallography of disulfide-tethered Rad4-DNA complex on undamaged DNA, temperature-jump perturbation spectroscopy Nature communications High 25562780
2016 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. Single-molecule fluorescence microscopy, quantum dot labeling, atomic force microscopy, in vivo UV resistance assays Molecular cell High 27720644
2016 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. Temperature-jump perturbation spectroscopy with fluorescence detection, mutagenesis of β-hairpin domain Proceedings of the National Academy of Sciences of the United States of America High 27035942
2019 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. X-ray crystallography, molecular dynamics simulations (4 μs) Nucleic acids research High 31106376
2019 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. Single-molecule fluorescence imaging on tethered DNA, analysis of diffusion coefficients vs. ionic strength Nucleic acids research Medium 31372632
2023 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. Cryo-EM structural determination of human XPC-TFIIH-XPA complex on damaged DNA Nature High 37076618
2021 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. Cryo-EM structure determination of Rad4-Rad23-Rad33/TFIIH complex on DNA Nature communications High 34099686
2017 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. Co-immunoprecipitation, live-cell imaging, in vitro pull-down with purified proteins, UV irradiation experiments Proceedings of the National Academy of Sciences of the United States of America Medium 28760956
2022 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. Mass spectrometry interactomics, Co-IP, live-cell imaging, PAR synthesis assays, chromatin remodeling assays Nature communications High 35963869
1994 Yeast Rad4 protein physically interacts with TFIIH (factor b) in vitro, suggesting Rad4/XPC directly recruits TFIIH as part of NER repairosome assembly. In vitro binding assay of Rad4 with purified TFIIH (factor b) subunits Molecular and cellular biology Medium 8196602
2004 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. Genetic mutant analysis in yeast, protein level measurements, ubiquitylation detection by Western blot Molecular and cellular biology Medium 15226437
2010 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. Co-immunoprecipitation in vivo and in vitro, yeast genetic analysis, UV sensitivity assays, protein stability measurements The Journal of biological chemistry Medium 20876584
2008 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. FRAP (fluorescence recovery after photobleaching), live-cell imaging of GFP-XPC, nuclear-cytoplasmic fractionation Journal of cell science Medium 18682493
2008 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. Direct binding assays, mutational analysis of Rad4-Rad33 interaction interface, yeast genetic analysis, UV repair assays DNA repair Medium 18387345
2015 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. Genome-wide ChIP-seq mapping of RAD23B, transcriptional profiling of SCC-depleted ESCs, co-immunoprecipitation of XPC with OCT4/SOX2 Proceedings of the National Academy of Sciences of the United States of America Medium 25901318
2018 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. ChIP-seq, RNA-seq, co-immunoprecipitation of XPC with KAT2A and E2F1, histone modification assays Nature communications Medium 29973595
2017 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. Genome-wide methylation analysis, biochemical TDG turnover assays, iPSC reprogramming experiments, Co-IP Genes & development Medium 28512237
2010 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. In vitro glycosylase activity assays, protein-protein interaction assays, comparison of XPC effects on human vs. E. coli TDG homologs Journal of nucleic acids Medium 20798892
2013 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. Co-immunoprecipitation, protein stability assays, XPC mutant analysis, proteasome association assays Molecular biology of the cell Medium 24258024
2017 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. Co-immunoprecipitation, chromatin fractionation, deubiquitylation assays, NER activity assays, UV irradiation experiments Oncotarget Medium 29228550
2009 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. Yeast genetic deletion analysis, ubiquitylation assays, substrate degradation assays, cellular fractionation Molecular biology of the cell Medium 19889839
2007 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. Permanganate footprinting assay, electrophoretic mobility shift assay (EMSA), reconstituted NER incision assay with six purified factors The EMBO journal Medium 17525733
1998 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. Affinity-purified epitope-tagged Rad4-Rad23, EMSA, in vitro NER complementation assay The Journal of biological chemistry Medium 9837874
1996 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. Heparin chromatography, gel filtration, native gel electrophoresis, immunodepletion, immunofluorescence Nucleic acids research Medium 8692695
2015 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. Single-particle electron microscopy, subunit tagging and deletion mapping Proceedings of the National Academy of Sciences of the United States of America Medium 26627236

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell 479 15882621
2007 Recognition of DNA damage by the Rad4 nucleotide excision repair protein. Nature 332 17882165
2005 DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation. Nucleic acids research 137 16030353
2015 Tripartite DNA Lesion Recognition and Verification by XPC, TFIIH, and XPA in Nucleotide Excision Repair. Molecular cell 134 26384665
2006 Rad4-Rad23 interaction with SWI/SNF links ATP-dependent chromatin remodeling with nucleotide excision repair. Nature structural & molecular biology 122 17013386
1996 Overproduction, purification, and characterization of the XPC subunit of the human DNA repair excision nuclease. The Journal of biological chemistry 119 8702634
2003 Critical DNA damage recognition functions of XPC-hHR23B and XPA-RPA in nucleotide excision repair. Molecular carcinogenesis 102 12949838
2008 Versatile DNA damage detection by the global genome nucleotide excision repair protein XPC. Journal of cell science 100 18682493
2015 SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair. Nature communications 99 26151477
1996 XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. Nucleic acids research 98 8692695
2014 Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity. Nature communications 97 24770583
2013 Associations of Lys939Gln and Ala499Val polymorphisms of the XPC gene with cancer susceptibility: a meta-analysis. International journal of cancer 87 23400628
2015 Kinetic gating mechanism of DNA damage recognition by Rad4/XPC. Nature communications 83 25562780
2005 DNA repair gene XPC genotypes/haplotypes and risk of lung cancer in a Chinese population. International journal of cancer 81 15700316
2005 Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 78 16081512
2007 The human DNA repair factor XPC-HR23B distinguishes stereoisomeric benzo[a]pyrenyl-DNA lesions. The EMBO journal 77 17525733
2000 Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Mutation research 75 10725660
2006 Polymorphisms in the DNA repair genes XPC, XPD, and XPG and risk of cutaneous melanoma: a case-control analysis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 73 17164380
2005 XPC polymorphisms and lung cancer risk. International journal of cancer 73 15729698
2016 Single-Molecule Imaging Reveals that Rad4 Employs a Dynamic DNA Damage Recognition Process. Molecular cell 72 27720644
2004 Rad23 stabilizes Rad4 from degradation by the Ub/proteasome pathway. Nucleic acids research 72 15601997
1998 Preferential binding of yeast Rad4.Rad23 complex to damaged DNA. The Journal of biological chemistry 71 9837874
2023 Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. Nature 67 37076618
1994 Yeast nucleotide excision repair proteins Rad2 and Rad4 interact with RNA polymerase II basal transcription factor b (TFIIH). Molecular and cellular biology 65 8196602
1991 Cloning and characterization of the rad4 gene of Schizosaccharomyces pombe; a gene showing short regions of sequence similarity to the human XRCC1 gene. Nucleic acids research 65 1762905
2007 Modulation of DNA damage/DNA repair capacity by XPC polymorphisms. DNA repair 64 17923445
2018 Molecular basis for damage recognition and verification by XPC-RAD23B and TFIIH in nucleotide excision repair. DNA repair 63 30174301
2008 Associations between XPC polymorphisms and risk of cancers: A meta-analysis. European journal of cancer (Oxford, England : 1990) 61 18771913
2012 Recognition of DNA damage by XPC coincides with disruption of the XPC-RAD23 complex. The Journal of cell biology 59 22431748
2011 The role of XPC: implications in cancer and oxidative DNA damage. Mutation research 59 21763452
2019 Structure and mechanism of pyrimidine-pyrimidone (6-4) photoproduct recognition by the Rad4/XPC nucleotide excision repair complex. Nucleic acids research 55 31106376
2019 Single-molecule visualization reveals the damage search mechanism for the human NER protein XPC-RAD23B. Nucleic acids research 55 31372632
2004 The initiative role of XPC protein in cisplatin DNA damaging treatment-mediated cell cycle regulation. Nucleic acids research 54 15107491
2016 Twist-open mechanism of DNA damage recognition by the Rad4/XPC nucleotide excision repair complex. Proceedings of the National Academy of Sciences of the United States of America 52 27035942
2006 UV-induced ubiquitylation of XPC complex, the UV-DDB-ubiquitin ligase complex, and DNA repair. Journal of molecular histology 51 16858626
2004 The NEF4 complex regulates Rad4 levels and utilizes Snf2/Swi2-related ATPase activity for nucleotide excision repair. Molecular and cellular biology 51 15226437
2008 XPC polymorphisms play a role in tissue-specific carcinogenesis: a meta-analysis. European journal of human genetics : EJHG 50 18285822
1997 Characterisation of the Schizosaccharomyces pombe rad4/cut5 mutant phenotypes: dissection of DNA replication and G2 checkpoint control function. Molecular & general genetics : MGG 48 9268024
2011 Histone deacetylases (HDACs) in XPC gene silencing and bladder cancer. Journal of hematology & oncology 46 21507255
2007 Long-term XPC silencing reduces DNA double-strand break repair. Cancer research 46 17363570
2007 A meta-analysis of DNA repair gene XPC polymorphisms and cancer risk. Journal of human genetics 45 18097734
2017 Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair. Proceedings of the National Academy of Sciences of the United States of America 44 28760956
2001 Peptide-N-glycanases and DNA repair proteins, Xp-C/Rad4, are, respectively, active and inactivated enzymes sharing a common transglutaminase fold. Human molecular genetics 44 11487565
2006 Genotypes, haplotypes and diplotypes of XPC and risk of bladder cancer. Carcinogenesis 39 17052994
2016 Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair. Oncotarget 37 27487145
2011 A new XPC gene splicing mutation has lead to the highest worldwide prevalence of xeroderma pigmentosum in black Mahori patients. DNA repair 36 21482201
2021 Cryo-EM structure of TFIIH/Rad4-Rad23-Rad33 in damaged DNA opening in nucleotide excision repair. Nature communications 35 34099686
2015 Functional and mechanistic studies of XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells. Proceedings of the National Academy of Sciences of the United States of America 35 25901318
2003 Defining the function of XPC protein in psoralen and cisplatin-mediated DNA repair and mutagenesis. Carcinogenesis 35 12807748
2019 XPC inhibition rescues cisplatin resistance via the Akt/mTOR signaling pathway in A549/DDP lung adenocarcinoma cells. Oncology reports 33 30628719
2008 XPC initiation codon mutation in xeroderma pigmentosum patients with and without neurological symptoms. DNA repair 33 18955168
1987 RAD4 gene of Saccharomyces cerevisiae: molecular cloning and partial characterization of a gene that is inactivated in Escherichia coli. Molecular and cellular biology 33 3550431
2018 BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands. eLife 32 30295604
2017 Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway. Chemical research in toxicology 32 28460163
1988 Cloning and nucleotide sequence analysis of the Saccharomyces cerevisiae RAD4 gene required for excision repair of UV-damaged DNA. Gene 32 3073107
2014 The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: is there a correlation? DNA repair 31 24784728
2008 Polymorphisms in XPC and ERCC2 genes, smoking and breast cancer risk. International journal of cancer 30 18196582
2007 Sequence variations in DNA repair gene XPC is associated with lung cancer risk in a Chinese population: a case-control study. BMC cancer 29 17498315
2004 The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response. Cell research 28 15353127
2020 XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature. Nature communications 27 33203900
2018 XPA, XPC, and XPD Modulate Sensitivity in Gastric Cisplatin Resistance Cancer Cells. Frontiers in pharmacology 27 30386247
2015 XPC inhibits NSCLC cell proliferation and migration by enhancing E-Cadherin expression. Oncotarget 27 25871391
2015 XPC: Going where no DNA damage sensor has gone before. DNA repair 27 26422135
2010 Yeast deubiquitinase Ubp3 interacts with the 26 S proteasome to facilitate Rad4 degradation. The Journal of biological chemistry 27 20876584
2018 XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1. Nature communications 26 29973595
2017 Inorganic arsenic inhibits the nucleotide excision repair pathway and reduces the expression of XPC. DNA repair 26 28237621
2014 Association of XPC polymorphisms and lung cancer risk: a meta-analysis. PloS one 26 24736739
2013 Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4(TopBP1). Molecular cell 26 24074952
2010 The DNA damage-binding protein XPC is a frequent target for inactivation in squamous cell carcinomas. The American journal of pathology 26 20616346
2008 XPC: its product and biological roles. Advances in experimental medicine and biology 26 19181110
2015 Architecture of the human XPC DNA repair and stem cell coactivator complex. Proceedings of the National Academy of Sciences of the United States of America 25 26627236
2019 XPC beyond nucleotide excision repair and skin cancers. Mutation research. Reviews in mutation research 23 31843141
2016 Polymorphisms in the XPC gene affect urinary bladder cancer risk: a case-control study, meta-analyses and trial sequential analyses. Scientific reports 23 27246180
2007 Reduced XPC messenger RNA level may predict a poor outcome of patients with nonsmall cell lung cancer. Cancer 23 17508409
2001 Differential ultraviolet-B-induced immunomodulation in XPA, XPC, and CSB DNA repair-deficient mice. The Journal of investigative dermatology 23 11442761
2017 Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage. Oncotarget 22 29228550
2010 Stimulation of DNA Glycosylase Activities by XPC Protein Complex: Roles of Protein-Protein Interactions. Journal of nucleic acids 22 20798892
2008 The NER protein Rad33 shows functional homology to human Centrin2 and is involved in modification of Rad4. DNA repair 22 18387345
2005 Associations between XPC expression, genotype, and the risk of head and neck cancer. Environmental and molecular mutagenesis 22 15657918
2004 Schizosaccharomyces pombe replication protein Cdc45/Sna41 requires Hsk1/Cdc7 and Rad4/Cut5 for chromatin binding. Chromosoma 22 15338237
2018 MicroRNA binding mediated Functional sequence variant in 3'-UTR of DNA repair Gene XPC in Age-related Cataract. Scientific reports 21 30315181
2012 The Rad4(TopBP1) ATR-activation domain functions in G1/S phase in a chromatin-dependent manner. PLoS genetics 21 22761595
2003 Delineating the position of rad4+/cut5+ within the DNA-structure checkpoint pathways in Schizosaccharomyces pombe. Journal of cell science 21 12865439
2022 XPC-PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair. Nature communications 20 35963869
2018 Enhanced spontaneous DNA twisting/bending fluctuations unveiled by fluorescence lifetime distributions promote mismatch recognition by the Rad4 nucleotide excision repair complex. Nucleic acids research 20 29267981
2013 XPC promotes MDM2-mediated degradation of the p53 tumor suppressor. Molecular biology of the cell 20 24258024
2011 Mcm10 interacts with Rad4/Cut5(TopBP1) and its association with origins of DNA replication is dependent on Rad4/Cut5(TopBP1). DNA repair 20 21945095
1994 Coupling of DNA replication and mitosis by fission yeast rad4/cut5. Journal of cell science. Supplement 20 7883793
1989 Nucleotide sequence of the wild-type RAD4 gene of Saccharomyces cerevisiae and characterization of mutant rad4 alleles. Journal of bacteriology 20 2649477
2016 Polymorphisms in the XPC gene and gastric cancer susceptibility in a Southern Chinese population. OncoTargets and therapy 19 27660469
2013 Genetic polymorphisms in RAD23B and XPC modulate DNA repair capacity and breast cancer risk in Puerto Rican women. Molecular carcinogenesis 19 23776089
2008 Oxidative DNA damage in XPC-knockout and its wild mice treated with equine estrogen. Chemical research in toxicology 19 18447394
2018 Lesion Sensing during Initial Binding by Yeast XPC/Rad4: Toward Predicting Resistance to Nucleotide Excision Repair. Chemical research in toxicology 18 30284444
2017 Regulation of DNA demethylation by the XPC DNA repair complex in somatic and pluripotent stem cells. Genes & development 18 28512237
2013 The association between XPC Lys939Gln gene polymorphism and urinary bladder cancer susceptibility: a systematic review and meta-analysis. Diagnostic pathology 18 23819639
2019 XPC protects against smoking- and carcinogen-induced lung adenocarcinoma. Carcinogenesis 17 30624620
2016 XPC deficiency is related to APE1 and OGG1 expression and function. Mutation research 17 26811994
2013 Association between CCND1 and XPC polymorphisms and bladder cancer risk: a meta-analysis based on 15 case-control studies. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 17 24264314
2009 Rad4 regulates protein turnover at a postubiquitylation step. Molecular biology of the cell 17 19889839
1994 Assignment of xeroderma pigmentosum group C (XPC) gene to chromosome 3p25. Genomics 17 8088800

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