ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation

Yana van der Weegen, Klaas de Lint, Diana van den Heuvel, Yuka Nakazawa, Tycho E. T. Mevissen, Janne J. M. van Schie, Marta San Martin Alonso, Daphne E. C. Boer, Román González-Prieto, Ishwarya V. Narayanan, Noud H. M. Klaassen, Annelotte P. Wondergem, Khashayar Roohollahi, Josephine C. Dorsman, Yuichiro Hara, Alfred C. O. Vertegaal, Job de Lange, Johannes C. Walter, Sylvie M. Noordermeer, Mats LjungmanTomoo Ogi, Rob M. F. Wolthuis*, Martijn S. Luijsterburg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4CSA ubiquitin ligase. How CRL4CSA is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4CSA for optimal RNAPII ubiquitylation. Drug–genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.
Original languageEnglish
Pages (from-to)595-607
Number of pages13
JournalNature Cell Biology
Volume23
Issue number6
DOIs
Publication statusPublished - 1 Jun 2021

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