RNA 3’end tailing safeguards cells against products of pervasive transcription termination

Abstract

Premature transcription termination yields a wealth of unadenylated (pA-) RNA. Although this can be targeted for degradation by the Nuclear EXosome Targeting (NEXT) complex, possible back-up pathways remain poorly understood. Here, we find RNA 3′ end uridylation and adenylation upon NEXT inactivation. U-tailed RNAs are generally short and modified by the cytoplasmic tailing enzymes, TUT4/7, following their PHAX-dependent nuclear export and prior to their degradation by the cytoplasmic exosome or the exoribonuclease DIS3L2. Longer RNAs are instead adenylated redundantly by enzymes TENT2, PAPOLA and PAPOLG. These transcripts are either degraded via the nuclear Poly(A) tail eXosome Targeting (PAXT) connection or exported by conventional factors and removed by the cytoplasmic exosome in a translation-dependent manner. Failure to do so decreases global translation and induces cell death. We conclude that post-transcriptional 3′ end modification and removal of excess pA- RNA is achieved by tailing enzymes and export factors shared with productive RNA pathways.