Journal Article

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

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

2021

Overview

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.Two side-by-side papers report that the transcription elongation factor ELOF1 drives transcription-coupled repair and prevents replication stress.

• Publisher: Nature Publishing Group
• Subject: Cellular stress response / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA damage / DNA repair / DNA-directed RNA polymerase / Elongation / Genetic screening / Lysine / Molecular modelling / R-loops / Repair / Replication / Ribonucleic acid / RNA / RNA polymerase / RNA polymerase II / Transcription-coupled repair / Ubiquitin / Ubiquitin-protein ligase