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

Marit E. Geijer, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Di Zhou, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Kathiresan Selvam, School of Molecular Biosciences, Washington State University, Pullman, WA, USA.
Barbara Steurer, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Chirantani Mukherjee, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Bastiaan Evers, Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Simona Cugusi, Mechanisms of Transcription Laboratory, The Francis Crick Institute, London, UK.
Marvin van Toorn, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Melanie van der Woude, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Roel C. Janssens, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Yannick P. Kok, Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Wenzhi Gong, Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
Anja Raams, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Calvin S. Lo, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Joyce H. Lebbink, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Bart Geverts, Erasmus Optical Imaging Center, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Dalton A. Plummer, School of Molecular Biosciences, Washington State University, Pullman, WA, USA.
Karel Bezstarosti, Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
Arjan F. Theil, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Richard Mitter, Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK.
Adriaan B. Houtsmuller, Erasmus Optical Imaging Center, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Wim Vermeulen, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Jeroen A. Demmers, Proteomics Center, Erasmus University Medical Center, Rotterdam, The Netherlands.
Shisheng Li, Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
Marcel A. van Vugt, Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Hannes Lans, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
René Bernards, Oncode Institute, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Jesper Q. Svejstrup, Mechanisms of Transcription Laboratory, The Francis Crick Institute, London, UK.
Arnab Ray Chaudhuri, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
John J. Wyrick, School of Molecular Biosciences, Washington State University, Pullman, WA, USA.
Jurgen A. Marteijn, Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands. J.Marteijn@erasmusmc.nl.

Document Type

Article

Publication Date

6-1-2021

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.

Publication Source (Journal or Book title)

Nature cell biology

First Page

608

Last Page

619

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