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PreprintCited by 45DNA Repair MechanismsGenomics and Chromatin DynamicsNuclear Structure and Function

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STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair

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van den Heuvel, Diana, Rodríguez-Martínez, Marta, van der Meer, Paula J., Moreno, Nicolas Nieto, Park, Jiyoung, Kim, Hyun-Suk, van Schie, Janne J.M., Wondergem, Annelotte P., D’Souza, Areetha, Yakoub, George, Herlihy, Anna E., Kashyap, Krushanka, Boissière, Thierry, Walker, Jane, Mitter, Richard, Apelt, Katja, de Lint, Klaas, Kirdök, Idil, Ljungman, Mats, Wolthuis, Rob M.F., Cramer, Patrick, Schärer, Orlando D., Kokic, Goran, Svejstrup, Jesper Q, Luijsterburg, Martijn S.·2024·Cell
DOI 10.1101/2024.07.22.604575PMC PMC12287594

Preprint — published as 10.1016/j.cell.2024.10.018

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Abstract

Summary: Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and TFIIH around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a new TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryo-EM and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.

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Metadata

Authors
van den Heuvel, D., Rodríguez-Martínez, M., van der Meer, P. J., Moreno, N. N., Park, J., Kim, H.-S., van Schie, J. J. M., Wondergem, A. P., D’Souza, A., Yakoub, G., Herlihy, A. E., Kashyap, K., Boissière, T., Walker, J., Mitter, R., Apelt, K., de Lint, K., Kirdök, I., Ljungman, M., Wolthuis, R. M. F., Cramer, P., Schärer, O. D., Kokic, G., Svejstrup, J. Q., & Luijsterburg, M. S.
Affiliations
  • Leiden University Medical Center (NL)
  • Institute for Basic Science (KR)
  • The Francis Crick Institute (GB)
  • University of Copenhagen (DK)
  • Amsterdam University Medical Centers (NL)
  • University of Michigan (US)
  • Max Planck Institute for Multidisciplinary Sciences (DE)
Corresponding author
  • Svejstrup, Jesper Q
  • Luijsterburg, Martijn S.
ORCID
Venue
Cell
Publisher
openRxiv
Published
2024-07-22
Volume
187
Issue
25
Pages
7107-7125.e25
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2024.07.22.604575
PMC
PMC12287594
OpenAlex
W4404375112
Cited by
45
References
1
Citations by year
2026: 23 · 2025: 16 · 2024: 6
FWCI
6.06
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Cell (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
  • PubMed Central (acceptedVersion)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by-nc)
  • PubMed Central (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
Funders
  • European Molecular Biology Organization (ALTF 911-2020)
  • Wellcome Trust (693327, NNF19OC0055875, FC001166, DNRF153)
  • Francis Crick Institute (FC001166, 693327, 10166, NNF19OC0055875, DNRF153)
  • Cancer Research UK (DNRF153, NNF19OC0055875, 693327, FC001166)
  • National Research Foundation
  • Deutsche Forschungsgemeinschaft (SPP‐1935, SFB 860)
  • Volkswagen Foundation
  • Danmarks Grundforskningsfond (FC001166, NNF19OC0055875, DNRF166, DNRF153, 693327)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ALW.016.161.320, 016.161.320, OCENW.M20.056, OCENW.M20)
  • Korea Basic Science Institute (IBS-R022-A1, P01CA092584)
  • Novo Nordisk (NNF19OC0055875)
  • Novo Nordisk Fonden (FC001166, DNRF153, NNF19OC0055875, 693327)
  • Institute for Basic Science (IBS-R022-A1)
  • University of Texas MD Anderson Cancer Center
  • Medical Research Council (FC001166, 693327, NNF19OC0055875, DNRF153)
  • European Research Council (101043815, 693023)
  • National Human Genome Research Institute (UM1HG009382)
  • National Cancer Institute (R01CA213214, P01CA092584)
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 › Nuclear Structure and Function
Keywords
transcription-coupled repair, RNA polymerase II, CSA, TFIIH, CSB, bulky DNA lesions, transcriptional stalling, protein complex structure

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