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

doi:10.1038/s41467-021-21520-w

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

Molecular Genetics

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	1342
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	26 Feb 2021
DOIs	https://doi.org/10.1038/s41467-021-21520-w
Publication status	Published - 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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A CSB-PAF1C axis restores processive transcription elongation after DNA damage repairFinal published version, 5.6 MBLicence: CC BY

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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. (2021). A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair. Nature Communications, 12(1), [1342]. https://doi.org/10.1038/s41467-021-21520-w

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title = "A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair",

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.",

author = "{van den Heuvel}, Diana and Spruijt, {Cornelia G.} and Rom{\'a}n Gonz{\'a}lez-Prieto and Angela Kragten and Paulsen, {Michelle T.} and Di Zhou and Haoyu Wu and Katja Apelt and {van der Weegen}, Yana and Kevin Yang and Madelon Dijk and Lucia Daxinger and Marteijn, {Jurgen A.} and Vertegaal, {Alfred C.O.} and Mats Ljungman and Michiel Vermeulen and Luijsterburg, {Martijn S.}",

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: {\textcopyright} 2021, The Author(s).",

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van den Heuvel, D, Spruijt, CG, González-Prieto, R, Kragten, A, Paulsen, MT, Zhou, D, Wu, H, Apelt, K, van der Weegen, Y, Yang, K, Dijk, M, Daxinger, L, Marteijn, JA, Vertegaal, ACO, Ljungman, M, Vermeulen, M & Luijsterburg, MS 2021, 'A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair', Nature Communications, vol. 12, no. 1, 1342. https://doi.org/10.1038/s41467-021-21520-w

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T1 - A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair

AU - van den Heuvel, Diana

AU - Spruijt, Cornelia G.

AU - González-Prieto, Román

AU - Kragten, Angela

AU - Paulsen, Michelle T.

AU - Zhou, Di

AU - Wu, Haoyu

AU - Apelt, Katja

AU - van der Weegen, Yana

AU - Yang, Kevin

AU - Dijk, Madelon

AU - Daxinger, Lucia

AU - Marteijn, Jurgen A.

AU - Vertegaal, Alfred C.O.

AU - Ljungman, Mats

AU - Vermeulen, Michiel

AU - Luijsterburg, Martijn S.

N1 - 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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N2 - 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.

AB - 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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DO - 10.1038/s41467-021-21520-w

M3 - Article

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JO - Nature Communications

JF - Nature Communications

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ER -

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

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