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

Diana van den Heuvel, Cornelia G. Spruijt, Román González-Prieto, Angela Kragten, Michelle T. Paulsen, Di Zhou, Haoyu Wu, Katja Apelt, Yana van der Weegen, Kevin Yang, Madelon Dijk, Lucia Daxinger, Jurgen A. Marteijn, Alfred C.O. Vertegaal, Mats Ljungman, Michiel Vermeulen, Martijn S. Luijsterburg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)
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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.

Original languageEnglish
Article number1342
JournalNature Communications
Volume12
Issue number1
Early online date26 Feb 2021
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
We acknowledge Haico van Attikum for providing U2OS GFP-RPB163 and U2OS TIR1 cells, Leon Mullenders for providing CS1AN-SV40 cells expressing GFP or GFP-CSB, Rick Wood for his generous gift of XPA antibody, and Brian Magnuson for valuable help with the BrU-seq analysis. This work was funded by an LUMC Research Fellowship and an NWO-VIDI grant (ALW.016.161.320) to M.S.L., a Leiden University Fund (LUF) grant to DvdH (W18355-2-EM), an NWO-VENI grant to C.G.S., an ERC grant to A.C.O.V. (310913), and a Dutch Cancer Society (KWF-Young Investigator Grant: 11367) to R.G.-P. The MV and JAM labs are part of the Oncode Institute, which is partly funded by the Dutch Cancer Society (KWF).

Publisher Copyright:
© 2021, The Author(s).

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