Affinage

XPA

DNA repair protein complementing XP-A cells · UniProt P23025

Length
273 aa
Mass
31.4 kDa
Annotated
2026-06-11
100 papers in source corpus 42 papers cited in narrative 41 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

XPA is the central scaffold of the nucleotide excision repair (NER) pre-incision complex, a zinc metalloprotein whose C4-type zinc finger (requiring Cys-103) is essential for proper folding and preferential binding to UV-, cisplatin-, and OsO4-damaged DNA (PMID:7526200, PMID:8538652). Rather than directly reading the lesion, XPA recognizes structurally distorted/bent duplex DNA through indirect backbone readout, while its partner RPA recognizes the disrupted base-paired strand, forming a combined damage-verification sensor; XPA contacts both damaged and undamaged strands and RPA enforces strand-specific binding that orients the XPF and XPG nucleases (PMID:11432842, PMID:11841234, PMID:12907715). XPA assembles the incision machinery through defined protein contacts: its G and E motifs bind the ERCC1–XPF endonuclease (a contact required for NER and exploited as a peptide inhibitor) (PMID:7891694, PMID:17948053), it recruits TFIIH to damaged DNA in a damage-dependent manner (PMID:9287294), and it organizes RPA through two distinct surfaces—an N-terminal disordered region engaging RPA32C and its DNA-binding domain engaging RPA70AB—that together fold the NER bubble into a U-shaped geometry (PMID:31925419, PMID:35969784). Within TFIIH, XPA binds between the XPB and XPD helicases and kinks the DNA, repositioning the lesion outside Core7 so that XPB and XPD track the damaged strand in opposite directions to drive XPD-mediated lesion verification (PMID:26384665, PMID:37076618). XPA is a rate-limiting NER factor whose abundance and activity are tightly regulated: HERC2 ubiquitin ligase targets XPA for degradation, antagonized by ATR-mediated Ser-196 phosphorylation upon damage, while SIRT1 deacetylates XPA at Lys-63/67/215 to promote ATR interaction and RPA32 binding, and circadian clock control drives oscillation of XPA-dependent repair (PMID:20670893, PMID:21193487, PMID:23178497, PMID:30327428, PMID:20304803). XPA also engages PARP1—binding poly(ADP-ribose), which lowers its DNA affinity, while reciprocally stimulating PARP1 activity—and beyond direct repair, XPA loss causes PARP-1 hyperactivation that depletes NAD+/SIRT1 and impairs mitophagy, revealing nuclear–mitochondrial crosstalk (PMID:24953096, PMID:24813611). XPA further contributes to ATR-dependent S-phase checkpoint activation through its lesion-recognition function (PMID:16675950).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1991 Medium

    Established that XPA is a nuclear protein whose loss correlates with the severity of the repair defect in xeroderma pigmentosum group A cells, anchoring the gene to NER capacity.

    Evidence Specific antibody immunoblotting and immunofluorescence in normal and XP-A cells

    PMID:1918083

    Open questions at the time
    • Did not define molecular activity
    • Two protein forms not mechanistically explained
    • No partner identified
  2. 1994 High

    Answered how XPA recognizes damage and showed it is a metal-dependent damage sensor, defining the zinc finger as essential for conformation and DNA-binding/NER activity.

    Evidence Recombinant XPA filter-binding, spectroscopy, Cys-103 mutagenesis, and microinjection complementation

    PMID:7526200

    Open questions at the time
    • Mechanism of lesion discrimination not resolved
    • Did not localize the minimal DNA-binding domain
  3. 1994 High

    Identified XPA as the recruiter of the ERCC1–XPF incision complex, establishing a scaffold function beyond passive damage binding.

    Evidence Yeast two-hybrid, in vitro binding, affinity-column depletion/complementation with repair-deficient extracts

    PMID:8197174 PMID:8197175

    Open questions at the time
    • Interaction interface mapped only coarsely
    • Order of complex assembly not defined
  4. 1995 High

    Demonstrated that the XPA–ERCC1 contact through the G and E motifs is mechanistically required for NER, with a dominant-negative deletion confirming necessity.

    Evidence Site-specific mutagenesis with in vitro repair synthesis and in vivo complementation

    PMID:7598728 PMID:7891694

    Open questions at the time
    • Atomic interface not yet defined
    • Functional consequence for nuclease positioning unknown at this stage
  5. 1995 High

    Established XPA–RPA as a cooperative damage-binding pair, mapping the RPA70-interaction region and showing the complex binds damaged DNA more tightly than XPA alone.

    Evidence In vitro and yeast two-hybrid binding, deletion mutagenesis, in vitro and in vivo NER assays

    PMID:7565690 PMID:7876167

    Open questions at the time
    • Structural basis of RPA contact not yet resolved
    • Stoichiometry of the complex undefined
  6. 1996 High

    Localized XPA's damaged-DNA binding to residues 98–219 and showed RPA and ERCC1 bind non-overlapping regions in a kinetically ordered ternary complex.

    Evidence Truncation analysis, CD spectroscopy, filter-binding, and surface plasmon resonance kinetics

    PMID:8538652 PMID:8972858

    Open questions at the time
    • Domain boundary later revised
    • Order of assembly within the full complex still incomplete
  7. 1997 Medium

    Showed XPA recruits TFIIH to damage sites, since TFIIH binds XPA·DNA complexes in a UV-damage-dependent manner despite lacking intrinsic damage preference.

    Evidence Filter binding and pull-down with damaged and undamaged DNA substrates

    PMID:9287294

    Open questions at the time
    • TFIIH-contacting residues of XPA not mapped
    • Single-lab evidence without structural detail
  8. 2000 High

    Provided structural and mechanistic basis for RPA-mediated recruitment and stabilization of XPA, and linked XPA to nuclear import via the GTPase XAB1.

    Evidence NMR of RPA32C, SPR with XPA-interaction-defective RPA mutant, yeast two-hybrid screen with deletion mapping

    PMID:10828957 PMID:11058119 PMID:11081631

    Open questions at the time
    • XAB1 evidence is Medium-confidence single lab
    • Full architecture of XPA–RPA on DNA still unresolved
  9. 2001 Medium

    Defined XPA–RPA as a double-check sensor detecting backbone bending and base-pair disruption simultaneously, recasting XPA as a verification/assembly factor rather than a lesion reader.

    Evidence EMSA with mispaired, non-hybridizing, and artificially bent DNA substrates; DDB stimulation of CPD excision in reconstituted NER

    PMID:11278856 PMID:11432842

    Open questions at the time
    • Indirect-readout model based on engineered substrates
    • DDB stimulation lesion-specificity mechanism unresolved
  10. 2002 Medium

    Resolved the strand topology of XPA binding (both strands contacted) versus RPA (undamaged strand) and indicated XPA functions as a homodimer in the RPA complex.

    Evidence Site-specific photocrosslinking; native gel filtration, PFO-PAGE, and mass spectrometry

    PMID:11841234 PMID:12390028

    Open questions at the time
    • Oligomeric state in the full NER complex contested
    • Functional role of dimerization not established in vivo
  11. 2003 Medium

    Showed XPA confers strand specificity on RPA binding at CPD lesions, providing the basis for correct positioning of dual-incision nucleases.

    Evidence NMR with RPA-A/AB domains on CPD-containing duplex substrates

    PMID:12907715

    Open questions at the time
    • Direct link to nuclease cleavage geometry inferred, not shown
    • Single-lab structural study
  12. 2007 High

    Defined the atomic XPA–ERCC1 interface and validated its functional importance by showing the XPA peptide inhibits NER.

    Evidence Crystal structure of ERCC1–XPA peptide, anisotropy binding, and cell-free excision inhibition

    PMID:17948053

    Open questions at the time
    • Structure limited to an isolated peptide
    • Context within the full complex not captured
  13. 2008 High

    Connected XPA to the global-genome damage-recognition factor DDB2, mapping a C-terminal interaction whose R207G disruption impairs damage recruitment and repair.

    Evidence In vitro binding, co-IP, R207G mutagenesis, reconstituted excision, and in vivo recruitment/repair assays

    PMID:19056823

    Open questions at the time
    • Temporal handoff from DDB to XPA not fully ordered
    • Overlap with PAR/TFIIH binding region not yet recognized at this stage
  14. 2010 High

    Established post-translational and circadian control of XPA abundance, identifying HERC2-mediated degradation, SIRT1-mediated deacetylation enhancing repair, and clock-driven oscillation of NER.

    Evidence Co-IP, in vitro deacetylation, acetylation-mimetic mutants, HERC2 knockdown, chromatin fractionation, and circadian-time tissue immunoblotting

    PMID:20304803 PMID:20670893 PMID:21193487

    Open questions at the time
    • Upstream signals triggering HERC2 dissociation only partly defined
    • Tissue specificity of circadian control unexplained
  15. 2012 High

    Identified ATR phosphorylation of XPA at Ser-196 as the switch that stabilizes XPA upon damage by blocking HERC2-mediated ubiquitination, and linked XPA to replication via a PCNA-interacting motif.

    Evidence S196A/S196D mutagenesis, co-IP, ubiquitination and chromatin assays; APIM mutagenesis with UV survival/repair and live imaging

    PMID:23152873 PMID:23178497

    Open questions at the time
    • APIM/replication role is Medium-confidence single lab
    • Crosstalk between phosphorylation and acetylation not integrated
  16. 2014 High

    Connected XPA to PARP1 signaling and revealed a non-canonical role: XPA loss drives PARP-1 hyperactivation depleting NAD+/SIRT1 and impairing mitophagy, defining nuclear–mitochondrial crosstalk.

    Evidence PAR-binding mutants, PARP1 activity assays, microirradiation; rescue by PARP inhibition/NAD+ in XPA-deficient cells and C. elegans; RASSF1A complex co-IP and repair assays

    PMID:24813611 PMID:24953096 PMID:25368379

    Open questions at the time
    • RASSF1A regulation is Medium-confidence single lab
    • Mechanistic basis of neurodegeneration specific to XPA loss not fully resolved
  17. 2014 High

    Refined the XPA DNA-binding domain to residues 98–239 and showed it binds Y-shaped ss/ds junctions with full-length affinity, undergoing a DNA-induced conformational change.

    Evidence Fluorescence anisotropy and 2D NMR with a C-terminal extension construct series

    PMID:25056193

    Open questions at the time
    • Functional contribution of the extended region in cells not isolated
    • Conformational change not yet mapped onto complex assembly
  18. 2015 High

    Defined XPA's role in lesion verification by showing it activates TFIIH unwinding of normal DNA but inhibits Core7 helicase at bulky lesions, forming a tripartite verification system with XPC and TFIIH.

    Evidence Reconstituted ten-subunit TFIIH/Core7 ATPase and helicase assays with defined lesions

    PMID:26384665

    Open questions at the time
    • Structural arrangement of XPA within TFIIH not yet visualized at this stage
  19. 2020 High

    Resolved the two-surface architecture by which XPA organizes RPA (XPA-N/RPA32C and XPA-DBD/RPA70AB), folding the NER bubble into a U-shape required for activity.

    Evidence NMR, SAXS, integrative modeling, and RPA70AB-disrupting mutations with biochemical and cellular NER assays

    PMID:31925419

    Open questions at the time
    • Atomic-resolution structure of the assembled bubble not yet available
    • Role of each contact in assembly order partly inferred
  20. 2022 High

    Assigned distinct functions to the two XPA–RPA contacts: XPA-N/RPA32C for initial complex association and XPA-DBD/RPA70AB for organizing dual incision, with additive effects when both are disrupted.

    Evidence Site-directed mutagenesis with in vitro and cell-based NER assays plus integrative SAXS/NMR modeling

    PMID:35969784

    Open questions at the time
    • Precise temporal ordering of incision events not directly observed
  21. 2023 High

    Provided the high-resolution structural mechanism: XPA binds between XPB and XPD and kinks the DNA to reposition the lesion for XPD verification, with the two helicases tracking the strand in opposite directions.

    Evidence Cryo-EM of human XPC–TFIIH–XPA–DNA complexes

    PMID:37076618

    Open questions at the time
    • Dynamics of lesion handoff to incision not captured
    • Regulatory modifications not visualized in the structure

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XPA's regulatory modification network (HERC2/ATR/SIRT1/PARP1) is integrated with the structurally defined pre-incision complex to control repair timing in vivo remains unresolved.
  • No structure of modified XPA within an assembled complex
  • Quantitative ordering of regulation versus assembly steps in cells undefined
  • Mechanistic basis of XPA-specific neurodegeneration via mitochondrial crosstalk incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0003677 DNA binding 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9909396 Circadian clock 1
Partners
DDB2ERCC1HERC2PARP1RPA32RPA70SIRT1TFIIH
Complex memberships
NER pre-incision complexXPA–ERCC1–XPF complexXPA–RPA complexXPC–TFIIH–XPA–DNA complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 XPA protein is a zinc metalloprotein that binds preferentially to UV-, cisplatin-, and OsO4-damaged DNA; a cysteine residue (Cys-103) in the C4-type zinc finger motif is indispensable for normal protein conformation and DNA-binding/NER activity, as shown by site-directed mutagenesis. Bacterially expressed recombinant XPA protein; nitrocellulose filter-binding assay for damaged DNA; atomic absorption and UV-CD spectroscopy; site-directed mutagenesis of Cys-103; microinjection complementation assay Mutation research High 7526200
1994 XPA and ERCC1 specifically interact both in vivo (yeast two-hybrid) and in vitro (recombinant proteins); the interaction domains were initially mapped, suggesting XPA recruits the ERCC1-containing incision complex to damaged DNA. Yeast two-hybrid system; in vitro binding with recombinant proteins; domain mapping Proceedings of the National Academy of Sciences of the United States of America High 8197174
1994 XPA forms a ternary complex with ERCC1 and ERCC4(XPF) heterodimer; an XPA affinity column depletes excision activity from HeLa extracts, which is restored by the XPA-bound fraction; the bound fraction complements ERCC1, ERCC4/XPF, and XPA-deficient extracts. XPA affinity column chromatography; in vitro complementation assay with cell-free extracts from repair-deficient cell lines Proceedings of the National Academy of Sciences of the United States of America High 8197175
1995 XPA interacts with both the 70-kDa and 34-kDa subunits of RPA at distinct sites; the RPA70-interaction domain maps to XPA residues 153–176, and deletion mutants within this region are deficient in RPA binding and highly defective in NER both in vitro and in vivo; the XPA–RPA complex has greater affinity for damaged DNA than XPA alone. In vitro binding assays; yeast two-hybrid; deletion mutagenesis; in vitro NER assay; in vivo complementation of XPA-deficient cells Molecular and cellular biology High 7565690
1995 XPA mutations that delete the G motif (Gly-72–Phe-75) or E motif (Glu-78–Glu-84) prevent association with ERCC1 and fail to complement XPA-deficient extracts in NER; the delta-G mutant acts as a dominant negative in wild-type extracts, indicating that the XPA–ERCC1 interaction is required for NER. Site-specific mutagenesis; in vitro ERCC1-binding assay; in vitro DNA repair synthesis assay; in vivo complementation Molecular and cellular biology High 7891694
1995 XPA interacts with the 34-kDa subunit of RPA, as identified by yeast two-hybrid; the RPA complex (70/34/11 kDa) associates with XPA, suggesting cooperation in early NER steps. Yeast two-hybrid; co-association with RPA complex The Journal of biological chemistry Medium 7876167
1995 Enhancement of XPA's damaged-DNA binding by ERCC1; XPA–ERCC1 interaction requires a stretch of consecutive glutamic acid residues in XPA; ERCC1 does not enhance binding when the truncated XPA-MF122 (lacking the protein–protein interaction region) is used. In vitro binding assay; yeast two-hybrid; electrophoretic mobility shift assay with truncation mutants Biochemical and biophysical research communications Medium 7598728
1996 The damaged-DNA binding domain of XPA is contained within residues 98–219 (MF122 fragment), which includes a C4-type zinc finger motif and has helix-rich secondary structure; this domain is sufficient for preferential binding to UV- or cisplatin-damaged DNA. Truncation analysis; nitrocellulose filter-binding assay; circular dichroism spectroscopy Mutation research High 8538652
1996 RPA and ERCC1 bind XPA at non-overlapping regions; a ternary RPA–XPA–ERCC1 complex forms in vitro; sequential binding occurs with RPA (KD ~19 nM) binding before ERCC1 (KD ~250 nM) based on surface plasmon resonance. In vitro binding/truncation assays; surface plasmon resonance biosensor; detection of ternary complex Nucleic acids research High 8972858
1997 TFIIH has some affinity for DNA but unlike XPA does not prefer UV-damaged DNA; TFIIH binds to XPA·DNA complexes in a UV damage-dependent manner via direct protein–protein interaction, suggesting XPA recruits TFIIH to damage sites. Filter binding assays; pull-down experiments; TFIIH interaction with XPA·DNA complexes The Journal of biological chemistry Medium 9287294
2000 RPA32 C-terminal globular domain interacts with XPA (and UNG2, RAD52) through a common structural surface; NMR structures of RPA32C free and in complex with UNG2 define the shared binding interface, establishing a structural basis for XPA recruitment by RPA. NMR structure determination; binding assays with XPA, UNG2, RAD52 Cell High 11081631
2000 XPA interacts with the novel cytoplasmic GTPase XAB1; XAB1 binds the N-terminal region of XPA (residues 30–34 required for nuclear localization); deletion of residues 30–34 abolishes XAB1 interaction, implicating XAB1 in nuclear import of XPA. Yeast two-hybrid screen of HeLa cDNA library; deletion mapping; immunofluorescence Nucleic acids research Medium 11058119
2000 RPA stabilizes the XPA–damaged DNA complex through protein–protein interaction; wild-type RPA enhances XPA binding to (6-4) photoproduct-containing DNA, whereas a mutant RPA (p34Δ33C) defective in XPA interaction fails to stabilize this complex. Surface plasmon resonance analysis; mutant RPA lacking XPA interaction domain Biochemistry High 10828957
2001 XPA–RPA complex acts as a double-check sensor: XPA binds rigidly bent duplexes (backbone distortion) via indirect readout, while RPA recognizes single-stranded regions (base pair disruption); together they simultaneously detect backbone and base pair distortion, supporting a damage-verification/assembly role rather than direct lesion recognition. DNA binding assays with substrates containing mispaired bases, non-hybridizing analogues, and artificially bent duplexes; electrophoretic mobility shift assays The EMBO journal Medium 11432842
2002 XPA forms a homodimer (XPA2) in solution under normal conditions; the dimer, not the monomer, forms the complex with RPA; XPA contains post-translational modifications as indicated by mass spectrometry. Native gel filtration chromatography; native PFO-PAGE; fluorescence spectroscopy; mass spectrometry; baculovirus-expressed protein Biochemistry Medium 12390028
2002 XPA contacts both the damaged and undamaged strands of a damaged duplex DNA, while RPA binds preferentially to the undamaged strand; demonstrated using photoreactive base analogues in specific substrates for site-specific crosslinking. Site-specific photocrosslinking with photoreactive base analogues; strand-specific analysis Biochemistry Medium 11841234
2003 In the presence of XPA, RPA binds specifically to the undamaged strand of CPD-containing duplex DNA, whereas without XPA both strands are bound non-specifically; this strand-specific interaction is relevant for guiding XPG/XPF nucleases to the correct cleavage sites. NMR spectroscopy with RPA-A and RPA-AB domains; CPD-containing duplex DNA substrates Nucleic acids research Medium 12907715
2005 XPA binds damaged DNA cooperatively: at lower concentrations as a monomer, at higher concentrations as a dimer; the dimer is the dominant form for efficient damage binding, with a Hill coefficient of ~1.9 and stepwise binding constants determined; RPA presence does not substantially enhance overall binding efficiency. Gel mobility shift assay; gel filtration chromatography; UV-crosslinking; fluorescence spectroscopy; competitive binding assay Biochemistry Medium 15882075
2007 Crystal structure of ERCC1 bound to an XPA peptide shows that only a small region of XPA interacts with ERCC1 with submicromolar affinity; this XPA peptide is a potent inhibitor of NER activity in a cell-free excision assay; the structure defines the XPA–ERCC1 binding interface. Crystal structure determination; fluorescence anisotropy binding assay; cell-free NER excision assay with peptide inhibitor The EMBO journal High 17948053
2008 DDB directly interacts with XPA primarily through the DDB2 subunit; XPA residues 185–226 are important for this interaction; the point mutation R207G in XPA disrupts DDB interaction in vitro and in vivo, abrogates DDB-stimulated CPD excision in a reconstituted system, and reduces XPA recruitment to damage sites in cells. In vitro binding assays; co-immunoprecipitation; site-directed mutagenesis (R207G); cell-free NER excision assay; in vivo repair assays Nucleic acids research High 19056823
2010 SIRT1 interacts with XPA, and this interaction is enhanced after UV irradiation; SIRT1 deacetylates XPA at Lys-63 and Lys-67 both in vitro and in cells; hyperacetylated XPA (K63/67Q mimetic) is NER-defective and shows increased UV sensitivity; SIRT1-mediated deacetylation of XPA enhances XPA–RPA32 interaction. Co-immunoprecipitation; in vitro deacetylation assay; XPA K63Q/K67Q acetylation-mimetic mutants; UV survival assay; in vivo NER assay Molecular cell High 20670893
2010 XPA protein undergoes circadian oscillation in mouse liver (but not testis) regulated at the transcriptional level by core circadian clock proteins including cryptochrome, and at the post-translational level by HERC2 ubiquitin ligase; consequently, cisplatin-adduct repair in liver extracts shows a circadian pattern. Immunoblotting of mouse liver/testis extracts at circadian time points; in vitro excision repair assays; analysis of cryptochrome and HERC2 role Proceedings of the National Academy of Sciences of the United States of America High 20304803
2010 XPA is a rate-limiting factor for NER in all human cell lines tested; its level is regulated post-translationally by the HECT-domain E3 ubiquitin ligase HERC2; DNA damage promotes tight association of XPA with chromatin and dissociation from HERC2, thereby inhibiting XPA ubiquitination and degradation; XPA is acetylated but in mouse liver only a small fraction is acetylated. siRNA knockdown of HERC2 and XPA; Tet-regulatable XPA expression; co-immunoprecipitation; chromatin fractionation; repair assays Nucleic acids research High 21193487
2012 ATR phosphorylates XPA at Ser-196, enhancing XPA stability by inhibiting HERC2-mediated ubiquitination and degradation; S196A (phosphodeficient) mutant shows persistent HERC2 association and enhanced ubiquitination; S196D (phosphomimetic) shows reduced HERC2 binding and delayed degradation; ATR-mediated phosphorylation also enhances chromatin retention of XPA and its interaction with binding partners after DNA damage. Site-directed mutagenesis (S196A, S196D); co-immunoprecipitation; ubiquitination assay; chromatin fractionation; XPA-deficient cell complementation Oncogene High 23178497
2012 XPA contains a functional PCNA-interacting motif (APIM); XPA colocalizes with PCNA in replication foci and is loaded on newly synthesized DNA in undamaged cells; XPA-deficient cells complemented with APIM-mutant XPA show increased UV sensitivity, reduced CPD and (6-4) photoproduct repair, and increased S-phase arrest; TFIIH subunit XPD and XPF are also loaded on DNA together with XPA. Live cell imaging; PCNA co-localization; XPA APIM mutagenesis; UV survival and repair assays in XPA-/- cells; chromatin loading assays PloS one Medium 23152873
2014 XPA binds poly(ADP-ribose) (PAR) non-covalently via specific basic amino acids in a conserved PAR-binding motif that overlaps the DDB2 and TFIIH interaction domains; XPA–PAR interaction lowers XPA's DNA-binding affinity; XPA strongly stimulates PARP1 enzymatic activity; PARP inhibition alters XPA-GFP recruitment to laser-induced DNA damage sites. PAR-binding assays with XPA mutants; biochemical PARP1 activity assay; live-cell microirradiation with XPA-GFP; co-immunoprecipitation The FEBS journal Medium 24953096
2014 Defective mitophagy in XPA-deficient cells is caused by PARP-1 hyperactivation leading to decreased NAD+–SIRT1–PGC-1α axis activity; PARP-1 inhibition or NAD+ precursor supplementation rescues mitochondrial defects and lifespan in xpa-1 nematodes; this nuclear-mitochondrial crosstalk pathway is absent in XPC (NER-deficient without neurodegeneration). In silico analysis; in vivo XPA-deficient cells and xpa-1 C. elegans; PARP inhibitor treatment; NAD+ supplementation; mitochondrial membrane potential assays Cell High 24813611
2014 Redefined DNA-binding domain of XPA extends to residue 239 (XPA 98–239), not residue 219 as previously reported; XPA(98–239) binds Y-shaped ssDNA/dsDNA junction with the same affinity as full-length XPA; the construct undergoes a conformational change upon DNA binding. Fluorescence anisotropy DNA-binding assay; 2D 15N-1H NMR; C-terminal extension series of XPA constructs Journal of the American Chemical Society High 25056193
2015 XPA activates unwinding of normal DNA by TFIIH Core7 but inhibits Core7 helicase activity in the presence of bulky lesions; bulky lesions inhibit XPB and XPD ATPase/helicase activities to promote NER; XPA, XPC, and TFIIH constitute a tripartite lesion verification mechanism. Reconstitution of human ten-subunit TFIIH and Core7; ATPase and helicase activity assays with defined substrates; NER assays with defined lesions Molecular cell High 26384665
2018 SIRT1 deacetylates XPA at Lys-63, Lys-67, and Lys-215 to promote XPA interactions with ATR; acetylation mimetics at these residues blunt UV-dependent ATR–XPA interaction even in the presence of cAMP; ATR-mediated phosphorylation of XPA at Ser-196 enhances cAMP-mediated NER and is promoted by SIRT1-mediated deacetylation. Co-immunoprecipitation; acetylation-mimetic and phosphomimetic/deficient mutants; UV-damage repair assays; cAMP signaling manipulation The Journal of biological chemistry Medium 30327428
2020 Two distinct interaction surfaces between XPA and RPA organize the NER preincision complex: (1) XPA N-terminal disordered domain with RPA32C, and (2) XPA DNA-binding domain with RPA70AB; mutations disrupting either site reduce NER activity, and combining both mutations additively inhibits NER; integrative structural modeling places the NER bubble in a U-shape with the two ssDNA/dsDNA junctions in proximity. NMR mapping of binding interfaces; X-ray scattering; comprehensive docking and refinement; XPA mutations inhibiting RPA70AB interaction; biochemical and cellular NER assays Nucleic acids research High 31925419
2022 Both XPA–RPA interaction sites (XPA-N/RPA32C and XPA-DBD/RPA70AB) are functionally required for NER; mutations in either site reduce NER in biochemical and cellular systems; combining mutations in both sites is additive; the XPA-N–RPA32C contact is important for initial XPA association with NER complexes, while XPA-DBD–RPA70AB contact organizes the complex for dual incision; the NER bubble assumes a U-shape geometry. Site-directed mutagenesis; in vitro NER biochemical assays; cell-based NER assays; integrative structural modeling with SAXS and NMR data Proceedings of the National Academy of Sciences of the United States of America High 35969784
2023 Cryo-EM structures reveal that XPA binds between XPB and XPD helicases of TFIIH Core7 and kinks the DNA duplex; this shifts XPC and the DNA lesion by nearly a helical turn relative to Core7, positioning the lesion outside Core7 for verification; XPB and XPD track the lesion-containing strand in opposite directions, pushing and pulling it into XPD for verification. Cryo-EM structure determination of human XPC–TFIIH–XPA–DNA complexes Nature High 37076618
2006 UV-induced ATR signaling (ATRIP translocation to UV damage sites, Chk1 phosphorylation, RPA phosphorylation and chromatin binding) is compromised in XPA-deficient human cells during S phase, but not in XPC-, CSB-, XPF-, or XPG-deficient cells; the lesion-recognition function of XPA (not damage processing) is sufficient for ATR-mediated S-phase checkpoint activation. Immunofluorescence for ATRIP translocation; western blotting for Chk1 and RPA phosphorylation; chromatin fractionation in NER-factor-deficient human cell lines The EMBO journal Medium 16675950
2009 Cep164 is recruited to CPD sites in a UV-dependent manner requiring XPA; UV irradiation enhances the physical interaction between Cep164 and XPA; Cep164 binds XPA residues 4–97; XPA(Δ10-88) mutant cells show aberrant Cep164/CPD co-localization and impaired UV-induced CHK1 phosphorylation. Co-immunoprecipitation; chromatin immunoprecipitation; immunofluorescence co-localization; XPA deletion mutants; CHK1 phosphorylation assay Cell cycle (Georgetown, Tex.) Medium 19197159
2014 RASSF1A forms a DNA damage-regulated complex with XPA and is required for full XPA repair activity; RASSF1A-deficient cells have impaired DNA repair; a cancer-associated RASSF1A SNP shows differential XPA binding and inhibits repair; RASSF1A and its SNP variant differentially regulate XPA acetylation and modulate the XPA–RPA70 complex. Co-immunoprecipitation; DNA repair assays in RASSF1A-deficient cells; SNP variant binding analysis; acetylation assays Molecular and cellular biology Medium 25368379
2000 Nickel(II), Cd(II), Co(II), and Cu(II) reduce XPA's DNA-binding ability; simultaneous treatment with Zn(II) largely prevents inhibition by Cd(II), Co(II), and Ni(II); Ni(II) does not form the same tetrahedral zinc finger complex as Zn(II). Nitrocellulose filter-binding assay for XPA activity; Zn(II) competition experiments Carcinogenesis Medium 11062174
2003 Ni(II) substitutes Zn(II) in the XPA zinc finger peptide (XPAzf) forming a square planar complex; this abolishes the normal tetrahedral zinc finger structure; Ni(II)-substituted XPAzf is highly susceptible to oxidative damage by H2O2; binding constants for Zn(II)/Ni(II) differ by ~800–2300-fold. Fluorescence spectroscopy; UV-vis and CD spectroscopy; HPLC oxidative damage analysis; synthetic XPAzf peptide Chemical research in toxicology Medium 12588196
1991 XPA protein (xpac) is localized in the nucleus of human cells; two forms (~40 and ~38 kDa) are detected; reduced or absent protein in XP group A cells correlates with repair defect severity; protein level does not increase after UV irradiation. Antibody against recombinant xpac protein; SDS-PAGE/immunoblotting; indirect immunofluorescence The Journal of biological chemistry Medium 1918083
2001 Full-length Xenopus XPA (xXPA) contains ordered internal core (residues ~Q85–I179) and disordered N- and C-terminal regions; mass spectrometry confirms no post-translational modifications in this species; xXPA binds cisplatin-modified ± mismatch DNA with at least 10-fold higher affinity than unmodified DNA. Time-resolved trypsin proteolysis; ESI-FTICR mass spectrometry; gel filtration chromatography; PONDR disorder prediction Protein science Medium 11344324 11420437
2001 DDB stimulates in vitro excision of CPDs (but not 6-4 photoproducts) in a reconstituted NER system; DDB elevates XPA binding to damaged DNA and forms a complex with damaged DNA together with XPA or XPA+RPA; the stimulation requires both XPA and RPA. In vitro NER excision assay; electrophoretic mobility shift assay; DNase I protection assay; addition of recombinant proteins to cell-free extracts The Journal of biological chemistry Medium 11278856

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 578 24813611
1994 Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. The Journal of clinical investigation 380 8040325
1995 Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature 344 7675086
1994 Specific association between the human DNA repair proteins XPA and ERCC1. Proceedings of the National Academy of Sciences of the United States of America 278 8197174
1999 Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Current biology : CB 248 10074455
1995 An interaction between the DNA repair factor XPA and replication protein A appears essential for nucleotide excision repair. Molecular and cellular biology 226 7565690
2000 Structural basis for the recognition of DNA repair proteins UNG2, XPA, and RAD52 by replication factor RPA. Cell 214 11081631
2010 Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 188 20304803
2010 SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Molecular cell 185 20670893
1994 Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins. Proceedings of the National Academy of Sciences of the United States of America 183 8197175
2004 Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. International journal of cancer 177 15095299
1995 DNA repair protein XPA binds replication protein A (RPA). The Journal of biological chemistry 169 7876167
2000 Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. Carcinogenesis 154 11062174
2001 Double-check probing of DNA bending and unwinding by XPA-RPA: an architectural function in DNA repair. The EMBO journal 148 11432842
2005 ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Molecular cancer 145 15882455
1994 The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage. Mutation research 137 7526200
2015 Tripartite DNA Lesion Recognition and Verification by XPC, TFIIH, and XPA in Nucleotide Excision Repair. Molecular cell 134 26384665
1997 A sequence in the N-terminal region of human uracil-DNA glycosylase with homology to XPA interacts with the C-terminal part of the 34-kDa subunit of replication protein A. The Journal of biological chemistry 134 9045683
2007 Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA. The EMBO journal 129 17948053
2003 Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA repair 117 12509265
1995 Mutations in XPA that prevent association with ERCC1 are defective in nucleotide excision repair. Molecular and cellular biology 113 7891694
2001 Aberrant mobility phenomena of the DNA repair protein XPA. Protein science : a publication of the Protein Society 106 11420437
2003 Critical DNA damage recognition functions of XPC-hHR23B and XPA-RPA in nucleotide excision repair. Molecular carcinogenesis 102 12949838
2010 Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein. Nucleic acids research 101 21193487
2002 Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions. Proceedings of the National Academy of Sciences of the United States of America 98 11972036
2001 Triplex-induced recombination in human cell-free extracts. Dependence on XPA and HsRad51. The Journal of biological chemistry 97 11278954
2001 Identification of intrinsic order and disorder in the DNA repair protein XPA. Protein science : a publication of the Protein Society 96 11344324
1997 DNA damage recognition by XPA protein promotes efficient recruitment of transcription factor II H. The Journal of biological chemistry 96 9287294
2016 XPA: A key scaffold for human nucleotide excision repair. DNA repair 93 27247238
1996 Identification of a damaged-DNA binding domain of the XPA protein. Mutation research 91 8538652
1996 Sequential binding of DNA repair proteins RPA and ERCC1 to XPA in vitro. Nucleic acids research 84 8972858
2006 Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling. The EMBO journal 80 16675950
2001 Damaged DNA-binding protein DDB stimulates the excision of cyclobutane pyrimidine dimers in vitro in concert with XPA and replication protein A. The Journal of biological chemistry 79 11278856
1997 The DNA damage-recognition problem in human and other eukaryotic cells: the XPA damage binding protein. The Biochemical journal 79 9359827
2006 XPA protein as a limiting factor for nucleotide excision repair and UV sensitivity in human cells. DNA repair 73 16413230
1992 Identification of splicing mutations of the last nucleotides of exons, a nonsense mutation, and a missense mutation of the XPAC gene as causes of group A xeroderma pigmentosum. Mutation research 72 1372103
2023 Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. Nature 67 37076618
2003 Mechanism of nickel assault on the zinc finger of DNA repair protein XPA. Chemical research in toxicology 67 12588196
2008 Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late-onset breast carcinoma. Molecular cancer 66 18990233
1997 Spontaneous liver tumors and benzo[a]pyrene-induced lymphomas in XPA-deficient mice. Molecular carcinogenesis 66 9180928
1997 Induction of DNA adducts and mutations in spleen, liver and lung of XPA-deficient/lacZ transgenic mice after oral treatment with benzo[a]pyrene: correlation with tumour development. Carcinogenesis 60 9450477
2014 Poly(ADP-ribose)-mediated interplay of XPA and PARP1 leads to reciprocal regulation of protein function. The FEBS journal 59 24953096
2006 XPA, haplotypes, and risk of basal and squamous cell carcinoma. Carcinogenesis 59 16513681
2012 Nucleotide excision repair is associated with the replisome and its efficiency depends on a direct interaction between XPA and PCNA. PloS one 58 23152873
2005 Human XPC-hHR23B interacts with XPA-RPA in the recognition of triplex-directed psoralen DNA interstrand crosslinks. Nucleic acids research 57 15914671
2012 Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair. Oncogene 56 23178497
2002 Dimerization of human XPA and formation of XPA2-RPA protein complex. Biochemistry 56 12390028
1995 Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein. Biochemical and biophysical research communications 56 7598728
2012 HIF1α regulated expression of XPA contributes to cisplatin resistance in lung cancer. Carcinogenesis 55 22467238
2020 XPA: DNA Repair Protein of Significant Clinical Importance. International journal of molecular sciences 54 32235701
2002 Strand-specific binding of RPA and XPA to damaged duplex DNA. Biochemistry 52 11841234
1993 High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia. American journal of human genetics 52 8105686
2013 Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in testicular germ cell tumours. British journal of cancer 51 23807173
2001 Binding of XPA and RPA to damaged DNA investigated by fluorescence anisotropy. Biochemistry 50 11258902
2000 RPA stabilizes the XPA-damaged DNA complex through protein-protein interaction. Biochemistry 50 10828957
2000 A novel cytoplasmic GTPase XAB1 interacts with DNA repair protein XPA. Nucleic acids research 50 11058119
1991 Identification and characterization of xpac protein, the gene product of the human XPAC (xeroderma pigmentosum group A complementing) gene. The Journal of biological chemistry 48 1918083
1991 xP1 and xP4. P-domain peptides expressed in Xenopus laevis stomach mucosa. The Journal of biological chemistry 48 1939167
2004 Association between the risk for lung adenocarcinoma and a (-4) G-to-A polymorphism in the XPA gene. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 45 15598786
2007 Nucleotide excision repair and the degradation of RNA pol II by the Caenorhabditis elegans XPA and Rsp5 orthologues, RAD-3 and WWP-1. DNA repair 44 18053776
2001 DNA repair-deficient Xpa and Xpa/p53+/- knock-out mice: nature of the models. Toxicologic pathology 43 11695546
1992 Molecular basis of group A xeroderma pigmentosum: a missense mutation and two deletions located in a zinc finger consensus sequence of the XPAC gene. Human genetics 43 1339397
2020 A key interaction with RPA orients XPA in NER complexes. Nucleic acids research 42 31925419
1998 Differential expression of the TFF-peptides xP1 and xP4 in the gastrointestinal tract of Xenopus laevis. Cell and tissue research 42 9394039
2015 TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts. Mutation research 39 25847421
2015 Role of the XPA protein in the NER pathway: A perspective on the function of structural disorder in macromolecular assembly. Computational and structural biotechnology journal 38 26865925
2001 Xpa and Xpa/p53+/- knockout mice: overview of available data. Toxicologic pathology 38 11695547
1995 Expression of a transfected DNA repair gene (XPA) in xeroderma pigmentosum group A cells restores normal DNA repair and mutagenesis of UV-treated plasmids. Carcinogenesis 38 7614689
2014 Redefining the DNA-binding domain of human XPA. Journal of the American Chemical Society 36 25056193
2002 The Caenorhabditis elegans XPA homolog of human XPA. Molecules and cells 36 12243352
2000 Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice. Mutation research 35 10838141
2009 UV-dependent interaction between Cep164 and XPA mediates localization of Cep164 at sites of DNA damage and UV sensitivity. Cell cycle (Georgetown, Tex.) 34 19197159
2014 The RASSF1A tumor suppressor regulates XPA-mediated DNA repair. Molecular and cellular biology 33 25368379
2006 A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. The British journal of dermatology 32 16792756
2008 Physical and functional interaction between DDB and XPA in nucleotide excision repair. Nucleic acids research 31 19056823
2005 Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg. DNA repair 31 15661658
2005 Cooperative interaction of human XPA stabilizes and enhances specific binding of XPA to DNA damage. Biochemistry 31 15882075
2002 The novel human HUEL (C4orf1) protein shares homology with the DNA-binding domain of the XPA DNA repair protein and displays nuclear translocation in a cell cycle-dependent manner. The international journal of biochemistry & cell biology 31 11906820
2002 Low amounts of the DNA repair XPA protein are sufficient to recover UV-resistance. Carcinogenesis 31 12082027
2022 Two interaction surfaces between XPA and RPA organize the preincision complex in nucleotide excision repair. Proceedings of the National Academy of Sciences of the United States of America 30 35969784
2017 CXCL1 Inhibition Regulates UVB-Induced Skin Inflammation and Tumorigenesis in Xpa-Deficient Mice. The Journal of investigative dermatology 30 28528167
1993 Genomic characterization of the human DNA excision repair-controlling gene XPAC. Gene 30 8294029
2020 Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours. BMC cancer 29 31906898
2010 Antimony impairs nucleotide excision repair: XPA and XPE as potential molecular targets. Chemical research in toxicology 29 20509621
2006 Induction of nevi and skin tumors in Ink4a/Arf Xpa knockout mice by neonatal, intermittent, or chronic UVB exposures. Cancer research 29 16510579
1993 A single-site mutation in the XPAC gene alters photoproduct recognition. Mutagenesis 29 8464385
2018 Sirtuin 1-mediated deacetylation of XPA DNA repair protein enhances its interaction with ATR protein and promotes cAMP-induced DNA repair of UV damage. The Journal of biological chemistry 28 30327428
2011 Both XPA and DNA polymerase eta are necessary for the repair of doxorubicin-induced DNA lesions. Cancer letters 28 21999933
2003 NMR study on the interaction between RPA and DNA decamer containing cis-syn cyclobutane pyrimidine dimer in the presence of XPA: implication for damage verification and strand-specific dual incision in nucleotide excision repair. Nucleic acids research 28 12907715
1991 Molecular cloning of human XPAC gene homologs from chicken, Xenopus laevis and Drosophila melanogaster. Biochemical and biophysical research communications 28 1764072
2018 XPA, XPC, and XPD Modulate Sensitivity in Gastric Cisplatin Resistance Cancer Cells. Frontiers in pharmacology 27 30386247
2008 XPA gene, its product and biological roles. Advances in experimental medicine and biology 27 19181108
2000 Three-dimensional structural views of damaged-DNA recognition: T4 endonuclease V, E. coli Vsr protein, and human nucleotide excision repair factor XPA. Mutation research 27 10946233
2002 Additive roles of XPA and MSH2 genes in UVB-induced skin tumorigenesis in mice. DNA repair 26 12531021
2000 Overexpression and purification of human XPA using a baculovirus expression system. Protein expression and purification 26 10833384
2010 Pterygium and genetic polymorphisms of the DNA repair enzymes XRCC1, XPA, and XPD. Molecular vision 25 20431719
2017 Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue. Toxicology and applied pharmacology 24 28552776
2010 XPA impacts formation but not proteasome-sensitive repair of DNA-protein cross-links induced by chromate. Mutagenesis 24 20410141
2008 Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation. Molecular carcinogenesis 24 18240296
2008 Interaction of nucleotide excision repair factors XPC-HR23B, XPA, and RPA with damaged DNA. Biochemistry. Biokhimiia 24 18774935

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