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

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. [Display omitted] •ARS2 transcription termination activity is independent of the INT and CPA pathways•The ZC3H4 restrictor factor interacts with ARS2 via a short linear motif (SLiM)•ARS2 is required for ZC3H4 recruitment to chromatin at a number of loci•ARS2-ZC3H4 triggers transcription termination and decay of the cognate RNA Rouviere et al. show that the RNA-binding protein ARS2, previously shown to act in early transcription termination, does so by recruiting the ZC3H4 “restrictor” factor to chromatin. The ARS2-ZC3H4 axis commits terminated transcripts for degradation by the nuclear exosome via a direct recruitment of the nuclear exosome targeting (NEXT) complex.