Person: Van der Weegen, Yana
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Publication ELOF1 Is a Transcription-Coupled DNA Repair Factor That Directs RNA Polymerase II Ubiquitylation
(Nature Publishing Group, 2021-06-09) Van der Weegen, Yana; de Lint, Klaas; van den Heuvel, Diana; Nakazawa, Yuka; Mevissen, Tycho; van Schie, Janne; San Martin Alonso, Marta; Boer, Daphne; González-Prieto, Roman; Narayanan, Ishwarya; Klaassen, Noud; Wondergem, Annelotte; Roohollahi, Kashayar; Dorsman, Josephine; Hara, Yuichiro; Vertegaal, Alfred; de Lange, Job; Walter, Johannes; Noordermeer, Sylvie; Ljungman, Mats; Ogi, Tomoo; Wolthuis, Rob; Luijsterburg, Martijn; LuijsterburgCells 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 at a single lysine (K1268) by the CRL4CSA ubiquitin ligase. How CRL4CSA is specifically directed toward the K1268 site is unknown. Here, we identify 5 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 the K1268 site, revealing ELOF1 as a specificity factor that interacts with and positions CRL4CSA for optimal RNAPII ubiquitylation. Drug-genetic interaction screening also reveals a CSB-independent compensatory pathway in which ELOF1 protects cells against DNA replication stress 10 by preventing DNA damage-induced R-loops. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between the transcriptional stress response and DNA replication.