Open AccessELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation
Author(s) -
Yana van der Weegen,
Klaas de Lint,
Diana van den Heuvel,
Yuka Nakazawa,
T.E.T. Mevissen,
Janne J.M. van Schie,
Marta San Martín Alonso,
Daphne E.C. Boer,
Román González-Prieto,
Ishwarya Venkata Narayanan,
Noud H. M. Klaassen,
Annelotte P. Wondergem,
Khashayar Roohollahi,
Josephine C. Dorsman,
Yuichiro Hara,
Alfred C.O. Vertegaal,
Job de Lange,
Johannes Walter,
Sylvie M. Noordermeer,
Mats Ljungman,
Tomoo Ogi,
Rob M. F. Wolthuis,
Martijn S. Luijsterburg
Publication year - 2021
Publication title -
nature cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 11.38
H-Index - 369
eISSN - 1476-4679
pISSN - 1465-7392
DOI - 10.1038/s41556-021-00688-9
Subject(s) - rna polymerase ii , microbiology and biotechnology , biology , transcription (linguistics) , dna repair , transcription factor , dna replication , ubiquitin ligase , ubiquitin , genetics , dna damage , transcription factor ii e , dna , gene , transcriptional regulation , promoter , gene expression , philosophy , linguistics
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 CRL4 CSA ubiquitin ligase. How CRL4 CSA 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 CRL4 CSA 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.