UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair
Abstract
Transcription-coupled nucleotide-excision repair (TC-NER) is a subpathway of NER that efficiently removes the highly toxic RNA polymerase II blocking lesions in DNA. Defective TC-NER gives rise to the human disorders Cockayne syndrome and UV-sensitive syndrome (UV(S)S). NER initiating factors are known to be regulated by ubiquitination. Using a SILAC-based proteomic approach, we identified UVSSA (formerly known as KIAA1530) as part of a UV-induced ubiquitinated protein complex. Knockdown of UVSSA resulted in TC-NER deficiency. UVSSA was found to be the causative gene for UV(S)S, an unresolved NER deficiency disorder. The UVSSA protein interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, resides in chromatin-associated TC-NER complexes and is implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme USP7 to TC-NER complexes. Together, these findings indicate that UVSSA-USP7–mediated stabilization of ERCC6 represents a critical regulatory mechanism of TC-NER in restoring gene expression.
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Backtracking of RNAPII allows correction of misincorporated nucleotides in RNA:DNA hybrids within transcription bubbles via cleavage of 3′ protruding RNA parts with mismatched nucleotides.
“Moreover, backtracking of RNAPII allows correction of misincorporated nucleotides in RNA:DNA hybrids within transcription bubbles via cleavage of 3′ protruding RNA parts with mismatched nucleotides.”
From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [104]
This event may be promoted by transcription factor TFIIS, which acts as a stimulator of RNAPII mRNA-cleavage activity.
“This event may be promoted by transcription factor TFIIS that acts as a stimulator of RNAPIIs mRNA-cleavage activity.”
From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [104]
USP7 helps delay ERCC6 degradation until the proper completion of ERCC6 function.
“Although ERCC6 degradation is necessary for the resumption of transcription following NER, it has been suggested that USP7 helps to delay this process until the proper completion of ERCC6 function (Schwertman et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Schwertman et al., 2012
In early TC-NER, USP7 interacts with and is recruited to lesions by UVSSA, and this interaction is important for USP7 to localize and stabilize ERCC6.
“In the early stages of TC-NER, USP7 interacts with and is recruited to lesions by the UVSSA scaffolding protein. This interaction is important for USP7 to localize and subsequently stabilize the adjacent protein, ERCC6 (Schwertman et al., 2012).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Schwertman et al., 2012
USP7 has a direct role in the DNA damage response via regulation of the nucleotide excision repair (NER) pathway.
“Aside from activating p53, multiple studies have suggested that USP7 also has a direct role in the DNA damage response via regulation of the nucleotide excision repair (NER) pathway (Sarasin, 2012; Schwertman et al., 2012; He et al., 2014; Higa et al., 2016; Zhu et al., 2020; Figure 3F).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Schwertman et al., 2012
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Self-citation
- Authors
- Schwertman, P., Lagarou, A., Dekkers, D. H. W., Raams, A., van der Hoek, A. C., Laffeber, C., Hoeijmakers, J. H. J., Demmers, J. A. A., Fousteri, M., Vermeulen, W., & Marteijn, J. A.
- Affiliations
- Erasmus MC (NL)
- Alexander Fleming Biomedical Sciences Research Center (GR)
- Corresponding author
- Vermeulen, Wim
- Marteijn, Jurgen A
- ORCID
- Venue
- Nature Genetics
- Published
- 2012-04-01
- Volume
- 44
- Issue
- 5
- Pages
- 598-602
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2092104135
- Cited by
- 279
- References
- 46
- Citations by year
- 2026: 19 · 2025: 17 · 2024: 23 · 2023: 15 · 2022: 22 · 2021: 26 · 2020: 16 · 2019: 14 · 2018: 13 · 2017: 12 · 2016: 25 · 2015: 17 · 2014: 24 · 2013: 22 · 2012: 14
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- USP7, transcription-coupled repair, Cockayne syndrome, ERCC6, CSB, deubiquitination, ubiquitination, RNA polymerase II, DNA repair, chromatin, gene expression
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, Ubiquitin-Specific Peptidase 7, Carrier Proteins, Cells, Cultured, Chromatin, Cockayne Syndrome, DNA Damage, DNA Repair, DNA Helicases, Humans, Mutation, RNA Polymerase II, Transcription, Genetic, Ultraviolet Rays, Ubiquitin, RNA, Small Interfering, Proteomics, Ubiquitin Thiolesterase, DNA Repair Enzymes, Immunoprecipitation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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