Human 5′ → 3′ exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites

Abstract

Eukaryotic protein-encoding genes possess poly(A) signals that define the end of the messenger RNA and mediate downstream transcriptional termination by RNA polymerase II (Pol II)¹. Termination could occur through an ‘anti-termination’ mechanism whereby elongation factors dissociate when the poly(A) signal is encountered, producing termination-competent Pol II^2,3. An alternative ‘torpedo’ model postulated that poly(A) site cleavage provides an unprotected RNA 5′ end that is degraded by 5′ → 3′ exonuclease activities (torpedoes) and so induces dissociation of Pol II from the DNA template^1,4. This model has been questioned because unprocessed transcripts read all the way to the site of transcriptional termination before upstream polyadenylation^5,6,7. However, nascent transcripts located 1 kilobase downstream of the human β-globin gene poly(A) signal are associated with a co-transcriptional cleavage (CoTC) activity⁸ that acts with the poly(A) signal to elicit efficient transcriptional termination. The CoTC sequence is an autocatalytic RNA structure that undergoes rapid self-cleavage⁹. Here we show that CoTC acts as a precursor to termination by presenting a free RNA 5′ end that is recognized by the human 5′ → 3′ exonuclease Xrn2. Degradation of the downstream cleavage product by Xrn2 results in transcriptional termination, as envisaged in the torpedo model.