ARS2 instructs early transcription termination-coupled RNA decay by recruiting ZC3H4 to nascent transcripts

Jérôme O. Rouvière, Anna Salerno-Kochan, Søren Lykke-Andersen, William Garland, Yuhui Dou, Om Rathore, Ewa Šmidová Molska, Guifen Wu, Manfred Schmid, Andrii Bugai, Lis Jakobsen, Kristina Žumer, Patrick Cramer, Jens S. Andersen, Elena Conti, Torben Heick Jensen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

The RNA-binding ARS2 protein is centrally involved in both early RNA polymerase II (RNAPII) transcription termination and transcript decay. Despite its essential nature, the mechanisms by which ARS2 enacts these functions have remained unclear. Here, we show that a conserved basic domain of ARS2 binds a corresponding acidic-rich, short linear motif (SLiM) in the transcription restriction factor ZC3H4. This interaction recruits ZC3H4 to chromatin to elicit RNAPII termination, independent of other early termination pathways defined by the cleavage and polyadenylation (CPA) and Integrator (INT) complexes. We find that ZC3H4, in turn, forms a direct connection to the nuclear exosome targeting (NEXT) complex, hereby facilitating rapid degradation of the nascent RNA. Hence, ARS2 instructs the coupled transcription termination and degradation of the transcript onto which it is bound. This contrasts with ARS2 function at CPA-instructed termination sites where the protein exclusively partakes in RNA suppression via post-transcriptional decay.

Original languageEnglish
JournalMolecular Cell
Volume83
Issue13
Pages (from-to)2240-2257
Number of pages18
ISSN1097-2765
DOIs
Publication statusPublished - Jul 2023

Keywords

  • ARS2
  • CPA complex
  • early transcription termination
  • INT complex
  • NEXT
  • PAXT
  • RNA decay
  • ZC3H4

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