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Molecular and Cellular Biology, May 2006, p. 3986-3996, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3986-3996.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pause Sites Promote Transcriptional Termination of Mammalian RNA Polymerase II

Natalia Gromak,{dagger} Steven West,{dagger} and Nick J. Proudfoot*

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom

Received 25 November 2005/ Returned for modification 4 January 2006/ Accepted 2 March 2006

Polymerase II (Pol II) transcriptional termination depends on two independent genetic elements: poly(A) signals and downstream terminator sequences. The latter may either promote cotranscriptional RNA cleavage or pause elongating Pol II. We demonstrate that the previously characterized MAZ4 pause element promotes Pol II termination downstream of a poly(A) signal, dependent on both the proximity of the pause site and poly(A) signal and the strength of the poly(A) signal. The 5'->3' exonuclease Xrn2 facilitates this pause-dependent termination by degrading the 3' product of poly(A) site cleavage. The human ß-actin gene also possesses poly(A) site proximal pause sequences, which like MAZ4 are G rich and promote transcriptional termination. Xrn2 depletion causes an increase in both steady-state RNA and Pol II levels downstream of the ß-actin poly(A) site. Taken together, we provide new insights into the mechanism of pause site-mediated termination and establish a general role for the 5'->3' exonuclease Xrn2 in Pol II termination.

* Corresponding author. Mailing address: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom. Phone: 44-1865-275-566. Fax: 44-1865-275-556. E-mail: nicholas.proudfoot{at}path.ox.ac.uk.

{dagger} N.G. and S.W. are joint first authors.

Molecular and Cellular Biology, May 2006, p. 3986-3996, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3986-3996.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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