Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Marit E. Geijer, Di Zhou, Kathiresan Selvam, Barbara Steurer, Chirantani Mukherjee, Bastiaan Evers, Simona Cugusi, Marvin van Toorn, Melanie van der Woude, Roel C. Janssens, Yannick P. Kok, Wenzhi Gong, Anja Raams, Calvin S.Y. Lo, Joyce H.G. Lebbink, Bart Geverts, Dalton A. Plummer, Karel Bezstarosti, Arjan F. Theil, Richard MitterAdriaan B. Houtsmuller, Wim Vermeulen, Jeroen A.A. Demmers, Shisheng Li, Marcel A.T.M. van Vugt, Hannes Lans, René Bernards, Jesper Q. Svejstrup, Arnab Ray Chaudhuri, John J. Wyrick, Jurgen A. Marteijn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

60 Citations (Scopus)

Abstract

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR–Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms.

Original languageEnglish
Pages (from-to)608-619
Number of pages12
JournalNature Cell Biology
Volume23
Issue number6
DOIs
Publication statusPublished - 9 Jun 2021

Bibliographical note

Funding Information:
We thank the Optical Imaging Center and the Proteomics Center of the Erasmus Medical Center for support with microscopes and mass spectrometry analysis. We thank the Advanced Sequencing Facility of the Francis Crick Institute for technical assistance with DRB/TTchem-seq. We acknowledge infrastructural support from the Josephine Nefkens Precision Cancer Treatment Program. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society and was funded by a grant from the Dutch Cancer Society (KWF grant 10506). This work was further funded by the Dutch organization for Scientific Research (NWO-ALW), which awarded a VIDI (864.13.004) and VICI (VI.C.182.025) grant to J.A.M. A.R.C. is supported by the Dutch Cancer Society (KWF grant 11008) and NWO VIDI (193.131). S.L. is funded by the National Science Foundation (MCB-1615550). J.J.W. is funded by the National Institute of Environmental Health Sciences (grants R01ES028698, R21ES029655 and R21ES029302). M.A.T.M.v.V. is funded by a grant from the European Research Council (ERC CoS grant 682421). H.L. is funded by The Netherlands Organization for Scientific Research (project number 711.018.007) and Cancergenomics.nl. W.V. was funded by a grant from the European Research Council (agreement 340988). J.Q.S. was supported by the Francis Crick Institute (which receives funding from Cancer Research UK (FC001166), the UK Medical Research Council (FC001166) and the Wellcome Trust (FC001166)) and by a grant from the European Research Council (agreement 693327).

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Fingerprint

Dive into the research topics of 'Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability'. Together they form a unique fingerprint.

Cite this