A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair

Diana Heuvel, Cornelia G. Spruijt, Román González-Prieto, Angela Kragten, Michelle T. Paulsen, Di Zhou, Haoyu Wu, Katja Apelt, Yana Weegen, Kevin Yang, Madelon Dijk, Lucia Daxinger, Jurgen A. Marteijn, Alfred C. O. Vertegaal, Mats Ljungman, Michiel Vermeulen and Martijn S. Luijsterburg ()
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Diana Heuvel: Leiden University Medical Center
Cornelia G. Spruijt: Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen
Román González-Prieto: Leiden University Medical Center
Angela Kragten: Leiden University Medical Center
Michelle T. Paulsen: University of Michigan
Di Zhou: Oncode Institute
Haoyu Wu: Leiden University Medical Center
Katja Apelt: Leiden University Medical Center
Yana Weegen: Leiden University Medical Center
Kevin Yang: University of Michigan
Madelon Dijk: Leiden University Medical Center
Lucia Daxinger: Leiden University Medical Center
Jurgen A. Marteijn: Oncode Institute
Alfred C. O. Vertegaal: Leiden University Medical Center
Mats Ljungman: University of Michigan
Michiel Vermeulen: Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen
Martijn S. Luijsterburg: Leiden University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21520-w

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