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Role for PSF in Mediating Transcriptional Activator-Dependent Stimulation of Pre-mRNA Processing In Vivo

Emanuel Rosonina ,^1,2,, Joanna Y. Y. Ip,^1,2, John A. Calarco,^1,2 Malina A. Bakowski,^1,2 Andrew Emili,^1,2,3 Susan McCracken,¹ Philip Tucker,⁴ C. James Ingles,^1,2 and Benjamin J. Blencowe^1,2,3*

Banting and Best Department of Medical Research,¹ Department of Molecular and Medical Genetics,² Proteomics and Bioinformatics Program, University of Toronto, 112 College Street, Toronto, Ontario M5G 1L6, Canada,³ Institute of Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, University of Texas, 1 University Station, Austin, Texas 78712-0162⁴

Received 22 February 2005/ Returned for modification 23 March 2005/ Accepted 10 May 2005

In a recent study, we provided evidence that strong promoter-bound transcriptional activators result in higher levels of splicing and 3'-end cleavage of nascent pre-mRNA than do weak promoter-bound activators and that this effect of strong activators requires the carboxyl-terminal domain (CTD) of RNA polymerase II (pol II). In the present study, we have investigated the mechanism of activator- and CTD-mediated stimulation of pre-mRNA processing. Affinity chromatography experiments reveal that two factors previously implicated in the coupling of transcription and pre-mRNA processing, PSF and p54^nrb/NonO, preferentially bind a strong rather than a weak activation domain. Elevated expression in human 293 cells of PSF bypasses the requirement for a strong activator to promote efficient splicing and 3'-end cleavage. Truncation of the pol II CTD, which consists of 52 repeats of the consensus heptapeptide sequence YSPTSPS, to 15 heptapeptide repeats prevents PSF-dependent stimulation of splicing and 3'-end cleavage. Moreover, PSF and p54^nrb/NonO bind in vitro to the wild-type CTD but not to the truncated 15-repeat CTD, and domains in PSF that are required for binding to activators and to the CTD are also important for the stimulation of pre-mRNA processing. Interestingly, activator- and CTD-dependent stimulation of splicing mediated by PSF appears to primarily affect the removal of first introns. Collectively, these results suggest that the recruitment of PSF to activated promoters and the pol II CTD provides a mechanism by which transcription and pre-mRNA processing are coordinated within the cell.

Present address: Department of Biological Sciences, Columbia University, 1119 Fairchild Center, MC 2413, New York, NY 10027.

E.R. and J.Y.Y.I. are co-first authors.

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