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

10 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

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