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

Nat Cell Biol. 2021 Jun;23(6):595-607. doi: 10.1038/s41556-021-00688-9. Epub 2021 Jun 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • DNA Damage*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA Repair*
  • Humans
  • Peptide Elongation Factor 1 / genetics
  • Peptide Elongation Factor 1 / metabolism*
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism*
  • Transcription Elongation, Genetic
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*


  • ERCC8 protein, human
  • IL17RB protein, human
  • Peptide Elongation Factor 1
  • Poly-ADP-Ribose Binding Proteins
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • RNA Polymerase II
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes