A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair
Open accessPublished version of a preprint
Abstract
Bulky DNA lesions in transcribed strands block RNA polymerase II (RNAPII) elongation and induce a genome-wide transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but how transcription is restored in the genome following DNA repair remains unresolved. Here, we find that the TCR-specific CSB protein loads the PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. Although dispensable for TCR-mediated repair, PAF1C is essential for transcription recovery after UV irradiation. We find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.
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Cites
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“Intensity-based absolute quantification (iBAQ) of protein amounts (Schwanhausser et al., 2011), indicates that at least 60% of the isolated CSB molecules associate with PAF1C and RNAPII subunits after exposure to UV light (Supplemental Figure 1B).”
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Paf1C regulates RNA polymerase II progression by modulating elongation rate
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Structure of complete Pol II–DSIF–PAF–SPT6 transcription complex reveals RTF1 allosteric activation
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- Authors
- van den Heuvel, D., Spruijt, C. G., González-Prieto, R., Kragten, A., Paulsen, M. T., Zhou, D., Wu, H., Apelt, K., van der Weegen, Y., Yang, K., Dijk, M., Daxinger, L., Marteijn, J. A., Vertegaal, A. C. O., Ljungman, M., Vermeulen, M., & Luijsterburg, M. S.
- Affiliations
- Radboud University Nijmegen (NL)
- Leiden University Medical Center (NL)
- University of Michigan (US)
- Oncode Institute (NL)
- Corresponding author
- Luijsterburg, Martijn S.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-02-26
- Volume
- 12
- Issue
- 1
- Pages
- 1342-1342
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7910549
- OpenAlex
- W3131547871
- Cited by
- 70
- References
- 5
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 12 · 2023: 12 · 2022: 10 · 2021: 11 · 2020: 2
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (acceptedVersion, cc-by)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Universiteit Leiden
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ALW.016.161.320, VI.C.182.025, 016.161.320)
- KWF Kankerbestrijding (11367)
- Leids Universitair Medisch Centrum
- Oncode Institute
- National Institute of General Medical Sciences (T32GM070449)
- FP7 Ideas: European Research Council (310913)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- CSB, Paf1 complex, RNA polymerase II, transcription elongation, transcription-coupled repair, DNA damage, UV irradiation, promoter-proximal pausing, processivity factor, genotoxic stress, transcriptional arrest
- MeSH terms
- Poly-ADP-Ribose Binding Proteins, Cell Nucleus, DNA, DNA Damage, DNA Repair, DNA Helicases, Humans, RNA Polymerase II, Transcription Factors, Transcription, Genetic, Ultraviolet Rays, DNA Repair Enzymes, Protein Interaction Maps
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