Effects of Transcription Elongation Rate and Xrn2 Exonuclease Activity on RNA Polymerase II Termination Suggest Widespread Kinetic Competition

The torpedo model of transcription termination asserts that the exonuclease Xrn2 attacks the 5′PO4-end exposed by nascent RNA cleavage and chases down the RNA polymerase. We tested this mechanism using a dominant-negative human Xrn2 mutant and found that it delayed termination genome-wide. Xrn2 nuclease inactivation caused strong termination defects downstream of most poly(A) sites and modest delays at some histone and U snRNA genes, suggesting that the torpedo mechanism is not limited to poly(A) site-dependent termination. A central untested feature of the torpedo model is that there is kinetic competition between the exonuclease and the pol II elongation complex. Using pol II rate mutants, we found that slow transcription robustly shifts termination upstream, and fast elongation extends the zone of termination further downstream. These results suggest that kinetic competition between elongating pol II and the Xrn2 exonuclease is integral to termination of transcription on most human genes. [Display omitted] •Xrn2 exonuclease inactivation inhibits pol II transcription termination genome wide•Slow and fast transcription elongation shift termination upstream and downstream•Kinetic competition of Xrn2 and pol II appears to dictate where termination occurs•The torpedo model is validated as a general termination mechanism for RNA pol II How are sites of transcription termination determined? Fong et al. show that where RNA polymerase II terminates downstream of polyadenylation sites is decided by a kinetic competition between the elongating polymerase and the RNA exonuclease Xrn2 that pursues it.