Affinage

UVSSA

UV-stimulated scaffold protein A · UniProt Q2YD98

Length
709 aa
Mass
80.6 kDa
Annotated
2026-06-11
22 papers in source corpus 18 papers cited in narrative 18 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

UVSSA is a scaffold protein essential for transcription-coupled nucleotide excision repair (TC-NER), the pathway that removes transcription-blocking DNA lesions encountered by elongating RNA polymerase II (PMID:22466611, PMID:35254895). UVSSA localizes to UV-induced lesions and associates with elongating RNAPII within chromatin-bound TC-NER complexes, where it stabilizes the master organizer ERCC6/CSB by recruiting the deubiquitinase USP7 into the complex (PMID:22466611, PMID:22466612). Within an ordered, cooperative assembly, CSB-bound stalled RNAPIIo recruits CSA, CSA then promotes UVSSA association with the stalled polymerase, and UVSSA is the critical factor that recruits the TFIIH complex to initiate repair (PMID:22902626, PMID:32355176); UVSSA engages TFIIH directly through the p62 subunit, undergoing a conformational change upon binding (PMID:37442507). UVSSA is itself accumulated at lesions independently of CSA/CSB via its VHS and DUF2043 domains, the latter binding the FACT subunit Spt16 to promote recruitment (PMID:30715484), and binds DNA and RNA directly through N- and C-terminal regions (PMID:36623745). UVSSA stability is controlled by ubiquitination at Lys414, where USP7 engagement protects it from proteasomal degradation, and the K414R substitution suppresses TC-NER deficiency (PMID:29323787); STK19 is recruited via CSA, bridges UVSSA with CSA and RPB1, promotes UVSSA Lys414 ubiquitination, and positions TFIIH for lesion excision [PMID:39353615, PMID:bio_10.1101_2024.07.22.604556]. Beyond UV repair, UVSSA supports MYC-driven RNAPII dynamics and is required for transcription-coupled repair of DNA interstrand crosslinks via its TFIIH interaction (PMID:33404608, PMID:39383571). Loss-of-function UVSSA mutations cause a defined TC-NER deficiency (PMID:22466610, PMID:31421932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 High

    Established UVSSA as a core TC-NER factor by showing it associates with elongating RNAPII and chromatin-bound repair complexes and stabilizes CSB by delivering USP7, answering how stalled-polymerase repair complexes are kept intact.

    Evidence SILAC proteomics, Co-IP, chromatin fractionation, complementation, and TCR repair assays across three concurrent studies in patient-derived and knockdown cells

    PMID:22466610 PMID:22466611 PMID:22466612

    Open questions at the time
    • Domain basis of RNAPII and USP7 binding not resolved
    • Order of factor recruitment relative to CSA/CSB undefined
    • Direct catalytic activity not demonstrated
  2. 2012 High

    Placed UVSSA downstream of CSA in the assembly hierarchy by showing CSA-dependent chromatin recruitment and TFIIH association, and that a CSA patient mutation abolishes UVSSA binding.

    Evidence Co-IP, chromatin fractionation, siRNA knockdown, and disease-mutant (CSA W361C) binding assays

    PMID:22902626

    Open questions at the time
    • Whether UVSSA-TFIIH binding is direct not established here
    • Mechanism of CSA-UVSSA interface unknown
  3. 2018 High

    Defined how UVSSA's own stability is regulated, showing Lys414 ubiquitination drives proteasomal degradation unless USP7 engagement protects UVSSA, linking UVSSA turnover to TC-NER proficiency.

    Evidence In vitro ubiquitination assay, K414R mutagenesis, proteasome inhibitor rescue, TC-NER functional assay

    PMID:29323787

    Open questions at the time
    • E3 ligase responsible for Lys414 ubiquitination not identified here
    • In vivo dynamics of the ubiquitination/deubiquitination cycle unresolved
  4. 2019 Medium

    Challenged the USP7-on-UVSSA model by reporting USP7 deubiquitinates CSB rather than UVSSA in vitro, refining which substrate USP7 stabilizes.

    Evidence In vitro deubiquitination assay with 6xHis-ubiquitin purification and UV time-course

    PMID:31775559

    Open questions at the time
    • Negative in vitro result not validated in cells
    • Discordant with prior Lys414/USP7 protection findings
  5. 2019 High

    Identified a CSA/CSB-independent recruitment route, showing UVSSA reaches lesions via its VHS and DUF2043 domains, with DUF2043 binding FACT subunit Spt16 to promote recruitment.

    Evidence Live-cell imaging with deletion mutants, SILAC interaction proteomics, siRNA knockdown, TC-NER repair assay

    PMID:30715484

    Open questions at the time
    • How Spt16-mediated and CSA-mediated recruitment are coordinated unclear
    • Relative contribution of each route to repair efficiency not quantified
  6. 2020 High

    Resolved the ordered TC-NER assembly pathway, demonstrating CSB recruits CSA via a CSA-interaction motif, CSA then loads UVSSA, and UVSSA recruits TFIIH stimulated by CSB and CSA.

    Evidence Isogenic CSB/CSA/UVSSA knockout cells with Co-IP, live-cell imaging, and quantitative interaction proteomics

    PMID:32355176

    Open questions at the time
    • Structural basis of UVSSA-TFIIH handoff not visualized
    • Whether TFIIH recruitment requires UVSSA nucleic-acid binding unknown
  7. 2021 Medium

    Extended UVSSA function beyond DNA repair, implicating it in MYC-driven RNAPII promoter dynamics independent of UV damage.

    Evidence RNAPII ChIP-seq, CRISPR/siRNA knockdown, ATM/CHK2 activation assay, RNAPII inhibitor rescue

    PMID:33404608

    Open questions at the time
    • Molecular mechanism linking UVSSA to MYC transcription undefined
    • Whether this role uses the TC-NER machinery unknown
  8. 2022 Medium

    Delineated the specificity of UVSSA, showing its knockout sensitizes cells to transcription-blocking lesions but not to oxidative agents or PARP inhibitors, unlike CSB.

    Evidence CRISPR-Cas9 knockout with survival assays and ATM activation readout

    PMID:35254895

    Open questions at the time
    • Basis of the functional divergence from CSB not mechanistically explained
  9. 2023 Medium

    Characterized UVSSA's intrinsic nucleic-acid engagement and its physical coupling to TFIIH, showing direct DNA/RNA binding by N- and C-terminal regions and conformational change of UVSSA on binding the TFIIH p62-PHD.

    Evidence EMSA, SPR, fluorescence binding with recombinant fragments; in vitro complex formation with SAXS/SANS

    PMID:36623745 PMID:37442507

    Open questions at the time
    • Cellular function of nucleic-acid binding not tested
    • Functional consequence of the TFIIH-induced conformational change unknown
  10. 2024 Medium

    Identified STK19 as a co-factor that bridges UVSSA with CSA and RPB1, promotes UVSSA Lys414 ubiquitination, stimulates CRL4-CSA-driven Pol II ubiquitylation, and positions TFIIH (via XPD) for lesion excision.

    Evidence Co-IP, in vitro interaction and ubiquitination assays, TC-NER repair assays, and cryo-EM structures (one at 1.9 A) with AlphaFold modeling and mutagenesis; several are preprints

    PMID:39353615 PMID:bio_10.1101_2024.07.22.604556 PMID:bio_10.1101_2024.07.22.604575 PMID:bio_10.1101_2024.07.22.604623

    Open questions at the time
    • Reports differ on whether STK19 affects UVSSA recruitment versus only downstream clearance
    • Cryo-EM/reconstitution findings are preprints awaiting peer review
  11. 2024 Medium

    Broadened UVSSA's repair scope, showing it is required for transcription-coupled repair of interstrand crosslinks through its TFIIH interaction.

    Evidence UVSSA knockout/knockdown, ICL drug sensitivity and single-ICL reporter assays, chromatin fractionation, Co-IP

    PMID:39383571

    Open questions at the time
    • How TC-ICR differs mechanistically from TC-NER downstream of UVSSA-TFIIH not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how UVSSA's intrinsic DNA/RNA binding, its USP7/STK19-controlled ubiquitination, and its conformational coupling to TFIIH are integrated into a single regulated lesion-excision event, and how its repair-independent transcriptional roles relate to its TC-NER scaffold function.
  • No unified structural model coupling nucleic-acid binding to TFIIH positioning
  • Discordant USP7 substrate findings unreconciled
  • Mechanism of repair-independent RNAPII regulation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0003677 DNA binding 1 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
CSA/ERCC8ERCC6/CSBRNA POLYMERASE II (RPB1/POLR2A)SPT16/SUPT16HSTK19TFIIH (P62/GTF2H1)USP7
Complex memberships
TC-NER complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 UVSSA (KIAA1530) is part of a UV-induced ubiquitinated protein complex and interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, and resides in chromatin-associated TC-NER complexes. UVSSA stabilizes the TC-NER master organizer ERCC6/CSB by recruiting the deubiquitinating enzyme USP7 to TC-NER complexes. SILAC-based proteomics, Co-IP, chromatin fractionation, knockdown with TC-NER repair assay, live-cell imaging Nature genetics High 22466611
2012 UVSSA forms a complex with USP7, stabilizes ERCC6/CSB, and restores the hypophosphorylated form of RNA polymerase II after UV irradiation. Knockdown of UVSSA destabilizes ERCC6/CSB in TCR. Co-IP, immunoblotting, microcell-mediated chromosome transfer complementation, cell-based TCR assay Nature genetics High 22466612
2012 UVSSA interacts with TC-NER machinery and stabilizes the ERCC6/CSB complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Exome sequencing, Co-IP, ubiquitination assay, TCR functional assay in patient-derived cells Nature genetics High 22466610
2012 UVSSA (KIAA1530) is recruited onto chromatin in a CSA-dependent manner after UV irradiation, interacts with CSA and the TFIIH complex, and is required for CSB stability following UV treatment. A CSA patient mutation (W361C) abolishes KIAA1530 binding and prevents CSB stabilization. Co-IP, chromatin fractionation, siRNA knockdown, UV sensitivity assay, mutant CSA binding assay The Journal of biological chemistry High 22902626
2018 UVSSA is mono-ubiquitinated in vitro at Lys414; USP7 deubiquitination activity protects UVSSA from proteasomal degradation. When UVSSA cannot interact with USP7 (via its TRAF-binding motif engaging USP7's N-terminal TRAF domain), UVSSA is poly-ubiquitinated and degraded, leading to TC-NER deficiency. Substitution K414R inhibits UVSSA degradation and suppresses TC-NER deficiency. In vitro ubiquitination assay, site-directed mutagenesis (K414R), proteasome inhibitor rescue, TC-NER functional assay The FEBS journal High 29323787
2019 USP7 does NOT deubiquitinate UVSSA in vitro; ubiquitinated UVSSA forms are not cleavable by USP7. USP7 deubiquitinates CSB (not UVSSA) to maintain CSB levels after UV damage. CSB overexpression stabilizes UVSSA but increases ubiquitinated UVSSA in insoluble chromatin. In vitro deubiquitination assay, 6xHis-tag ubiquitin purification, immunoblotting, UV irradiation time-course Cell cycle (Georgetown, Tex.) Medium 31775559
2019 UVSSA accumulates at transcription-blocking lesions independently of CSA and CSB, mediated by its VHS and DUF2043 domains. The DUF2043 domain mediates interaction with Spt16 subunit of the histone chaperone FACT, and Spt16 promotes UVSSA recruitment and TC-NER repair without affecting CSB recruitment. Live-cell imaging, UVSSA deletion mutants, quantitative interaction proteomics (SILAC), siRNA knockdown, TC-NER repair assay Nucleic acids research High 30715484
2020 TCR assembly is sequential and cooperative: RNAPIIo-bound CSB recruits CSA via a newly identified CSA-interaction motif (CIM); CSA then facilitates UVSSA association with stalled RNAPIIo; UVSSA is the key factor that recruits the TFIIH complex in a manner stimulated by CSB and CSA. Isogenic knockout cell lines (CSB, CSA, UVSSA), Co-IP, live-cell imaging, quantitative interaction proteomics Nature communications High 32355176
2021 UVSSA has a role in supporting MYC-dependent RNA polymerase II dynamics independent of UV-induced DNA damage. UVSSA knockdown/knockout reduces RNAPII promoter occupancy under MYC-driven transcription, and the synthetic sick interaction with MYC is diminished by attenuating RNAPII activity, implicating UVSSA in regulating RNAPII during oncogene-driven transcription. RNAPII ChIP-seq, CRISPR/siRNA knockdown, ATM/CHK2 activation assay, RNAPII inhibitor rescue The Journal of cell biology Medium 33404608
2022 CRISPR-mediated UVSSA knockout cells are sensitive to transcription-blocking lesions and activate ATM signaling, but are not sensitive to oxidative agents or PARP inhibitors (unlike CSB knockout), defining a specific functional role for UVSSA in TC-NER but not in broader DNA damage responses. CRISPR-Cas9 knockout, cell survival assays, ATM activation (signaling assay) Proceedings of the National Academy of Sciences of the United States of America Medium 35254895
2023 Human UVSSA directly binds DNA and RNA via at least two nucleic acid-binding regions: the N-terminal domain and a C-terminal tail region (residues 606–662). These regions, far apart in sequence, are predicted to be in close structural proximity. EMSA, SPR, fluorescence-based binding assays with recombinant protein fragments, biophysical characterization Archives of biochemistry and biophysics Medium 36623745
2023 UVSSA forms a stable complex with the pleckstrin-homology domain of the p62 subunit of TFIIH (p62-PHD) in vitro, and TFIIH binding causes significant conformational changes in UVSSA as measured by small-angle X-ray and neutron scattering. In vitro complex formation, small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), radius of gyration measurement International journal of biological macromolecules Medium 37442507
2024 STK19 is recruited to DNA damage sites via direct interaction with CSA, promotes UVSSA ubiquitination at Lys414 which is required for TC-NER, and stimulates TFIIH recruitment through direct interaction with TFIIH independently of UVSSA ubiquitination. Co-IP, in vitro interaction assay, ubiquitination assay, TC-NER repair assay, siRNA/CRISPR knockdown Nucleic acids research Medium 39353615
2024 UVSSA is critical for transcription-coupled repair of DNA interstrand crosslinks (TC-ICR); UVSSA interacts with transcribing Pol II, CSA, CSB, and TFIIH at ICL damage sites, and UVSSA–TFIIH interaction specifically is required for ICL repair. UVSSA knockout/knockdown, ICL drug sensitivity assay, fluorescence-based single-ICL reporter assay, chromatin fractionation, Co-IP DNA repair Medium 39383571
2024 Cryo-EM structures of the TC-NER complex show that STK19 bridges CSA with UVSSA, RPB1, and downstream DNA, and is integral to the Pol II-TC-NER complex. STK19 stimulates CRL4-CSA E3 ligase activity resulting in efficient Pol II ubiquitylation and correct UVSSA and TFIIH binding. Cryo-EM structure determination, live-cell imaging, Co-IP interaction studies, TC-NER functional assay bioRxivpreprint Medium bio_10.1101_2024.07.22.604556
2024 Cryo-EM and mutational analysis show STK19 positions itself between RNAPII, UVSSA, and CSA in the TC-NER complex. Loss of STK19 does not affect initial TCR complex assembly (including UVSSA recruitment) or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance and downstream repair. Cryo-EM, mutational analysis, TC-NER factor recruitment assay, RNAPII ubiquitylation assay bioRxivpreprint Medium bio_10.1101_2024.07.22.604575
2024 Cell-free TC-NER reconstitution in frog egg extract shows that UVSSA is required for error-free repair of a site-specific lesion in a transcribed plasmid. A 1.9 Å cryo-EM structure places STK19 at the interface of CSA and RPB1 within the TC-NER complex, and AlphaFold modeling predicts STK19 interacts with XPD of TFIIH to position it ahead of Pol II; disrupting this interface impairs repair. Cell-free reconstitution in Xenopus egg extract, site-specific lesion reporter, cryo-EM at 1.9 Å, AlphaFold modeling, mutagenesis bioRxivpreprint Medium bio_10.1101_2024.07.22.604623
2019 A truncating UVSSA mutation (p.Trp347*) causes mislocalization of UVSSA protein from the nucleus to the cytoplasm, demonstrating that the C-terminal portion of UVSSA is required for nuclear localization. Immunofluorescence of wild-type and truncated UVSSA constructs in mammalian cells, immunoblotting Journal of dermatological science Low 31421932

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair. Nature genetics 223 22466611
2012 Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair. Nature genetics 191 22466612
2012 Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair. Nature genetics 176 22466610
2020 The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II. Nature communications 145 32355176
2012 KIAA1530 protein is recruited by Cockayne syndrome complementation group protein A (CSA) to participate in transcription-coupled repair (TCR). The Journal of biological chemistry 57 22902626
2013 UVSSA and USP7, a new couple in transcription-coupled DNA repair. Chromosoma 38 23760561
2019 FACT subunit Spt16 controls UVSSA recruitment to lesion-stalled RNA Pol II and stimulates TC-NER. Nucleic acids research 37 30715484
2012 UVSSA and USP7: new players regulating transcription-coupled nucleotide excision repair in human cells. Genome medicine 25 22621766
2024 STK19 is a transcription-coupled repair factor that participates in UVSSA ubiquitination and TFIIH loading. Nucleic acids research 24 39353615
2018 Inhibition of UVSSA ubiquitination suppresses transcription-coupled nucleotide excision repair deficiency caused by dissociation from USP7. The FEBS journal 22 29323787
2019 USP7-mediated deubiquitination differentially regulates CSB but not UVSSA upon UV radiation-induced DNA damage. Cell cycle (Georgetown, Tex.) 15 31775559
2016 A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA. DNA repair 11 27043179
2021 The UVSSA complex alleviates MYC-driven transcription stress. The Journal of cell biology 8 33404608
2024 UVSSA facilitates transcription-coupled repair of DNA interstrand crosslinks. DNA repair 6 39383571
2019 UV-sensitive syndrome: Whole exome sequencing identified a nonsense mutation in the gene UVSSA in two consanguineous pedigrees from Pakistan. Journal of dermatological science 6 31421932
2023 Structural characterization of transcription-coupled repair protein UVSSA and its interaction with TFIIH protein. International journal of biological macromolecules 5 37442507
2022 The UVSSA protein is part of a genome integrity homeostasis network with links to transcription-coupled DNA repair and ATM signaling. Proceedings of the National Academy of Sciences of the United States of America 5 35254895
2023 Transcription coupled DNA repair protein UVSSA binds to DNA and RNA: Mapping of nucleic acid interaction sites on human UVSSA. Archives of biochemistry and biophysics 4 36623745
2020 Publisher Correction: The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II. Nature communications 2 33159085
2024 Transcription-Coupled Repair of DNA Interstrand Crosslinks by UVSSA. bioRxiv : the preprint server for biology 1 37214867
2023 A Homozygous Nonsense Variant in UVSSA Causes UV-sensitive Syndrome from Very Large Kindred: The First Report from Iran. Advanced biomedical research 1 38192884
2024 A Cockayne-Syndrome-Like Phenotype with a Homozygous Truncating UVSSA Variant: Might This Be a New Cause? Molecular syndromology 0 39119453

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