Aberrant RNA methylation triggers recruitment of an alkylation repair complex

Ning Tsao, Joshua R. Brickner, Rebecca Rodell, Adit Ganguly, Matthew Wood, Clement Oyeniran, Tanveer Ahmad, Hua Sun, Albino Bacolla, Lisheng Zhang, Valentina Lukinović, Jennifer M. Soll, Brittany A. Townley, Alexandre G. Casanova, John A. Tainer, Chuan He, Alessandro Vindigni, Nicolas Reynoird, Nima Mosammaparast

Research output: Contribution to journalArticlepeer-review

Abstract

Central to genotoxic responses is their ability to sense highly specific signals to activate the appropriate repair response. We previously reported that the activation of the ASCC-ALKBH3 repair pathway is exquisitely specific to alkylation damage in human cells. Yet the mechanistic basis for the selectivity of this pathway was not immediately obvious. Here, we demonstrate that RNA but not DNA alkylation is the initiating signal for this process. Aberrantly methylated RNA is sufficient to recruit ASCC, while an RNA dealkylase suppresses ASCC recruitment during chemical alkylation. In turn, recruitment of ASCC during alkylation damage, which is mediated by the E3 ubiquitin ligase RNF113A, suppresses transcription and R-loop formation. We further show that alkylated pre-mRNA is sufficient to activate RNF113A E3 ligase in vitro in a manner dependent on its RNA binding Zn-finger domain. Together, our work identifies an unexpected role for RNA damage in eliciting a specific response to genotoxins.

Original languageEnglish (US)
Pages (from-to)4228-4242.e8
JournalMolecular cell
Volume81
Issue number20
DOIs
StatePublished - Oct 21 2021

Keywords

  • ASCC
  • E3 ligase
  • RNA methylation
  • RNF113A
  • alkylation
  • genome stability
  • transcription

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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