Transcriptional Activators Control Splicing and 3′-End Cleavage Levels

We have investigated whether transcriptional activators influence the efficiency of constitutive splicing and 3′-end formation, in addition to transcription levels. Remarkably, strong activators result in higher levels of splicing and 3′-cleavage than weak activators and can control the efficiency of these steps in pre-mRNA processing separately. The pre-mRNA processing stimulatory property of activators is dependent on their binding to promoters, but is not an indirect consequence of the levels of transcripts produced. Moreover, stimulation of splicing and cleavage by a strong activator operates by a mechanism that requires the carboxyl-terminal domain of RNA polymerase II. The splicing stimulatory property of activators was observed for unrelated transcripts and for separate introns within a transcript, indicating a possible general role for strong activators in facilitating pre-mRNA processing levels. The results suggest that the efficiency of constitutive splicing and 3′-end cleavage is closely coordinated with transcription levels by promoter-bound activators. We have investigated whether transcriptional activators influence the efficiency of constitutive splicing and 3′-end formation, in addition to transcription levels. Remarkably, strong activators result in higher levels of splicing and 3′-cleavage than weak activators and can control the efficiency of these steps in pre-mRNA processing separately. The pre-mRNA processing stimulatory property of activators is dependent on their binding to promoters, but is not an indirect consequence of the levels of transcripts produced. Moreover, stimulation of splicing and cleavage by a strong activator operates by a mechanism that requires the carboxyl-terminal domain of RNA polymerase II. The splicing stimulatory property of activators was observed for unrelated transcripts and for separate introns within a transcript, indicating a possible general role for strong activators in facilitating pre-mRNA processing levels. The results suggest that the efficiency of constitutive splicing and 3′-end cleavage is closely coordinated with transcription levels by promoter-bound activators. The generation of mature mRNA involves the addition of an m7G cap at the 5′-end, splicing, and cleavage and polyadenylation at the 3′-end of precursor (pre-)mRNAs. Although these steps can occur in isolation of each other, the majority of pre-mRNA processing occurs as RNA polymerase II (pol II) 1The abbreviations used are: pol II, RNA polymerase II; CTD, COOH-terminal domain; ESE, exonic splicing enhancer; DBD, DNA binding domain; TAT, Tat transactivator; Ad2ML, adenovirus 2 major late promoter; HIV, human immunodeficiency virus; FBP, Far upstream element binding protein. is transcribing. This is evident from numerous microscopy studies, in which the removal of most introns is observed to coincide with nascent transcript synthesis, as well as from more recent studies that demonstrate that transcription and pre-mRNA processing steps are physically coupled and can influence one another (1Hirose Y. Manley J.L. Genes Dev. 2000; 14: 1415-1429Crossref PubMed Google Scholar, 2Cramer P. Srebrow A. Kadener S. Werbajh S. de la Mata M. Melen G. Nogues G. Kornblihtt A.R. FEBS Lett. 2001; 498: 179-182Crossref PubMed Scopus (71) Google Scholar, 3Maniatis T. Reed R. Nature. 2002; 416: 499-506Crossref PubMed Scopus (928) Google Scholar). The largest subunit of pol II contains a carboxyl-terminal domain (CTD), which in mammals consists of 52 repeats of the heptapeptide consensus sequence YSPTSPS (4Corden J.L. Cadena D.L. Ahearn Jr., J.M. Dahmus M.E. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 7934-7938Crossref PubMed Scopus (238) Google Scholar, 5Allison L.A. Moyle M. Shales M. Ingles C.J. Cell. 1985; 42: 599-610Abstract Full Text PDF PubMed Scopus (444) Google Scholar). Pol II at the stage of transcription initiation is associated with a large holoenzyme complex, which is recruited to promoters by sequence-specific transcriptional activators (6Lu H. Flores O. Weinmann R. Reinberg D. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 10004-10008Crossref PubMed Scopus (248) Google Scholar, 7Koleske A.J. Young R.A. Nature. 1994; 368: 466-469Crossref PubMed Scopus (533) Google Scholar, 8Kim Y.J. Bjorklund S. Li Y. Sayre M.H. Kornberg R.D. Cell. 1994; 77: 599-608Abstract Full Text PDF PubMed Scopus (889) Google Scholar, 9Pan G. Aso T. Greenblatt J. J. Biol. Chem. 1997; 272: 24563-24571Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 10Ossipow V. Tassan J.P. Nigg E.A. Schibler U. Cell. 1995; 83: 137-146Abstract Full Text PDF PubMed Scopus (178) Google Scholar). In some cases, stimulation of transcription by activators requires the CTD (11Allison L.A. Ingles C.J. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2794-2798Crossref PubMed Scopus (90) Google Scholar, 12Scafe C. Chao D. Lopes J. Hirsch J.P. Henry S. Young R.A. Nature. 1990; 347: 491-494Crossref PubMed Scopus (123) Google Scholar, 13Gerber H.P. Hagmann M. Seipel K. Georgiev O. West M.A. Litingtung Y. Schaffner W. Corden J.L. Nature. 1995; 374: 660-662Crossref PubMed Scopus (137) Google Scholar). Recent work has demonstrated that the CTD is also important for pre-mRNA processing. Truncation of the CTD in vivo reduces the efficiency of capping, splicing, and 3′-end formation (14Cho E.J. Takagi T. Moore C.R. Buratowski S. Genes Dev. 1997; 11: 3319-3326Crossref PubMed Scopus (373) Google Scholar, 15McCracken S. Fong N. Yankulov K. Ballantyne S. Pan G. Greenblatt J. Patterson S. Wickens M. Bentley D.L. Nature. 1997; 385: 357-361Crossref PubMed Scopus (740) Google Scholar, 16McCracken S. Fong N. Rosonina E. Yankulov K. Brothers G. Siderovski D. Hessel A. Foster S. Shuman S. Bentley D.L. Genes Dev. 1997; 11: 3306-3318Crossref PubMed Scopus (433) Google Scholar). Moreover, purified pol II, or the CTD itself, can stimulate splicing as well as the 3′-end processing of transcripts in vitro (17Hirose Y. Manley J.L. Nature. 1998; 395: 93-96Crossref PubMed Scopus (300) Google Scholar, 18Hirose Y. Tacke R. Manley J.L. Genes Dev. 1999; 13: 1234-1239Crossref PubMed Scopus (174) Google Scholar, 19Zeng C. Berget S.M. Mol. Cell. Biol. 2000; 20: 8290-8301Crossref PubMed Scopus (61) Google Scholar). Consistent with these results, factors involved in capping, splicing, and 3′-end formation have been found to interact with the CTD (1Hirose Y. Manley J.L. Genes Dev. 2000; 14: 1415-1429Crossref PubMed Google Scholar, 3Maniatis T. Reed R. Nature. 2002; 416: 499-506Crossref PubMed Scopus (928) Google Scholar, 20Corden J.L. Patturajan M. Trends Biochem. Sci. 1997; 22: 413-416Abstract Full Text PDF PubMed Scopus (149) Google Scholar). It is not known at which stage of transcription different pre-mRNA processing components are recruited to transcription complexes, nor how CTD-associated components influence pre-mRNA processing. The 3′-end cleavage polyadenylation stimulatory factor (CPSF) interacts with the general transcription factor TFIID during transcription initiation (21Dantonel J.C. Murthy K.G. Manley J.L. Tora L. Nature. 1997; 389: 399-402Crossref PubMed Scopus (255) Google Scholar), as well as with the CTD (15McCracken S. Fong N. Yankulov K. Ballantyne S. Pan G. Greenblatt J. Patterson S. Wickens M. Bentley D.L. Nature. 1997; 385: 357-361Crossref PubMed Scopus (740) Google Scholar), indicating that it is recruited to transcription initiation complexes prior to its role in cleavage. A number of splicing or splicing-related factors have recently been detected in association with holoenzyme complexes involved in transcription initiation, further suggesting that specific pre-mRNA processing components may be recruited to active genes at the stage of transcription initiation (22Robert F. Blanchette M. Maes O. Chabot B. Coulombe B. J. Biol. Chem. 2002; 277: 9302-9306Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 23Emili A. Shales M. McCracken S. Xie W. Tucker P.W. Kobayashi R. Blencowe B.J. Ingles C.J. RNA. 2002; 8: 1102-1111Crossref PubMed Scopus (146) Google Scholar). Recent work has also shown that the type of promoter or activator used to drive transcription can influence the level of inclusion of alternative exons in transfected pre-mRNA reporters (24Cramer P. Caceres J.F. Cazalla D. Kadener S. Muro A.F. Baralle F.E. Kornblihtt A.R. Mol. Cell. 1999; 4: 251-258Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 25Kadener S. Cramer P. Nogues G. Cazalla D. de la Mata M. Fededa J.P. Werbajh S.E. Srebrow A. Kornblihtt A.R. EMBO J. 2001; 20: 5759-5768Crossref PubMed Scopus (111) Google Scholar, 26Auboeuf D. Honig A. Berget S.M. O'Malley B.W. Science. 2002; 298: 416-419Crossref PubMed Scopus (313) Google Scholar, 27Nogues G. Kadener S. Cramer P. Bentley D. Kornblihtt A. J. Biol. Chem. 2002; 277: 43110-43114Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar), suggesting that events occurring as early as promoter recognition may play an important role in the regulation of splicing. However, whether transcriptional activators can also influence the efficiency of constitutive pre-mRNA processing reactions, including splicing and 3′-end formation, has not been investigated. In the present study we provide evidence that tethering transcriptional activators of different strengths to the promoter of pre-mRNA reporters can modulate the efficiency of splicing and 3′-end cleavage. Stronger activators resulted in higher levels of splicing of constitutive introns, as well as higher levels of 3′-end cleavage, than weak activators. Stronger transcriptional activators were also found to stimulate 3′-end cleavage independently of splicing. The differential stimulation of splicing and cleavage by these activators was not a consequence of the different levels of transcripts produced but, instead, appeared to be because of an inherent functional property of the transcriptional activator. Our results also demonstrate that the increased level of splicing and cleavage promoted by a strong activator is dependent on the CTD of pol II, indicating an important role for this domain in mediating the effects of promoters on pre-mRNA processing. In summary, our results suggest that an important role of transcriptional activators is to modulate pre-mRNA processing efficiency in accordance with transcript levels. Transfections and RNA Analysis—Human 293 cells grown on 15-cm plates were transfected using FuGENE-6 (Roche Diagnostics) as per the manufacturer's instructions, with 5 μg of reporter, 0.5 μg of Gal4-(fusion) expression plasmid (or as indicated in Fig. 2), 0.5 μg of pSP-VA, and the appropriate empty vector to maintain equal amounts of DNA between samples. Cells were harvested 48 h post-transfection and RNA was isolated as previously described (28Yankulov K. Blau J. Purton T. Roberts S. Bentley D.L. Cell. 1994; 77: 749-759Abstract Full Text PDF PubMed Scopus (209) Google Scholar). In Fig. 3, 5 μg of α-amanitin-resistant pol II expression plasmid or the corresponding empty vector was transfected in addition to the above plasmids. 2.5 was to the h and RNA was isolated another 48 were as previously were detected by and using a from on a and RNA were as were to the number of the or were by the corresponding or was using μg of RNA and the sequence which is to a sequence of the transcriptional within the of the pre-mRNA CTD of pol II is for splicing and 3′-end cleavage. of splicing and cleavage, as described in the to Fig. for transcripts by α-amanitin-resistant RNA pol II a type CTD (pol 3, and or CTD (pol and and by or as levels of transcripts in cells not α-amanitin-resistant pol II and A of the is shown for to with and are shown in the as described in the to Fig. present in transcripts by pol II, and by in the of the of pol II as a consequence of in and are because of α-amanitin-resistant pol and pol because the levels of these are in of pol II described (24Cramer P. Caceres J.F. Cazalla D. Kadener S. Muro A.F. Baralle F.E. Kornblihtt A.R. Mol. Cell. 1999; 4: 251-258Abstract Full Text Full Text PDF PubMed Scopus (257) Google and expression for J. S. A. H. S. D. Reinberg D. D. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and J. H. McCracken S. P. Greenblatt J. Bentley D. Mol. Cell. Biol. PubMed Scopus Google Scholar). and were by the of and S. M. Blencowe B.J. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google with a corresponding to the of plasmid (28Yankulov K. Blau J. Purton T. Roberts S. Bentley D.L. Cell. 1994; 77: 749-759Abstract Full Text PDF PubMed Scopus (209) Google Scholar), using and reporters were by of in polymerase the a that to upstream of the and a to of the The were and was a from A. and has been previously described (24Cramer P. Caceres J.F. Cazalla D. Kadener S. Muro A.F. Baralle F.E. Kornblihtt A.R. Mol. Cell. 1999; 4: 251-258Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). for 5′-end, splicing, and have been previously described (28Yankulov K. Blau J. Purton T. Roberts S. Bentley D.L. Cell. 1994; 77: 749-759Abstract Full Text PDF PubMed Scopus (209) Google Scholar, S. M. Blencowe B.J. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google Scholar). The for 3′-end cleavage and was by of including of the cleavage of the late polyadenylation and upstream including in and the using as a and as a which contains the RNA polymerase promoter sequence for in vitro transcription from the The was with and and the and of the in the plasmid with and with RNA polymerase an that result in from transcripts with of for and for RNA. The for splicing of introns and 2 from was by of of 2 and the including upstream and The used were as a and as a which contains the RNA polymerase promoter sequence for in vitro transcription from the However, the was with and and was the corresponding in the of with and transcription with RNA the plasmid an and from with the at at 2 and Pol II was by and of to of an α-amanitin-resistant of the largest subunit of pol II from F. M. C. O. PubMed Scopus Google expression plasmid The sequence is by an upstream sequence and and for CTD heptapeptide to 52 pol were by and the and of pol and more of the of pol II expression are from the and whether transcriptional activators influence pre-mRNA processing we different to the promoter of a pre-mRNA from exons and of the The pre-mRNA requires an exonic splicing in for processing in vitro and in vivo S. M. Blencowe B.J. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google Scholar, K. K. H. Y. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M. T. Science. PubMed Scopus Google Scholar, J.M. J.P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Li Y. Blencowe B.J. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). whether activators or processing we splicing and 3′-end cleavage levels of with or a of repeats The pre-mRNA contains an promoter and upstream binding for the binding domain and can be by different transcriptional The reporters were transfected human 293 with expression for a strong from the or a weak domain corresponding to a of S. R. P. Mol. Cell. Biol. 13: PubMed Scopus Google to Fig. RNA isolated from the transfected cells was by using for of splicing or 3′-end cleavage to Fig. as well as a for of a pol to which as an control for efficiency and RNA and with an the transcription of the were also to whether initiation at the and not of to and to as well as transcript were from In addition to transcription than by of and with also resulted in a higher of RNA and a higher of RNA of the pre-mRNA and also to the in Fig. which of the in Fig. as well as separate and activators described stimulation of splicing and 3′-end cleavage, by and was also observed in the of the Fig. and also to shown in Fig. The in levels of splicing and cleavage from of transcription by was not because of differential of in the of or transcripts by these activators not whether activators can influence pre-mRNA we from the Tat Far upstream element binding and with each as well as to and each domain resulted in a different level of splicing and 3′-end cleavage of the as well as different transcript levels. The levels of splicing and cleavage were observed with strong from and levels were observed with weak from TAT, and to the in Fig. and cleavage levels each and by as as between the different of the specific activator used to drive the of an splicing and 3′-end cleavage to in Fig. of which activator is used to drive splicing and cleavage levels are closely However, the activator used to drive independently of the of an ESE, the level of splicing and cleavage of a in the of whether the activators can modulate 3′-end formation in the of splicing because splicing is in the of cleavage on the pre-mRNA S. M. Blencowe B.J. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google Scholar), it was not possible to whether activators modulate splicing independently of cleavage for this activator was with an of the pre-mRNA and were to cleavage levels with the 3′-end that different activators resulted in cleavage levels of the that were to observed with the was the in stimulation of cleavage of the in Fig. and transcriptional activators can modulate 3′-end cleavage levels in the of splicing. by in splicing and 3′-end cleavage efficiency were not a consequence of initiation of The of by or transcription of the were by to was detected at the 2 and of the of transcripts by each activator by using an the transcription also that initiation at the and not at upstream not the different levels of splicing and 3′-end cleavage observed with each activator are not a consequence of transcription and of of the activators described above resulted in a in the level of splicing or cleavage of the transcripts by an adenovirus major late promoter that binding not also Fig. Moreover, the increased levels of splicing and cleavage were not an indirect consequence of the increased levels of splicing and cleavage were more the were from the promoter with the produced levels of transcripts of transcription and levels are and resulted in levels of splicing and cleavage stimulation of the but at higher levels of transcripts than further whether the level of splicing and cleavage of transcripts the type of activator used to drive than the specific level of transcripts we whether the efficiency of splicing and cleavage is is at levels expression to an transcript levels are than levels not the of to or to RNA 2 and not results demonstrate that the higher levels of splicing and cleavage from with the transcription an functional property of the domain than an indirect consequence of its in increased transcript levels. A for the Pol II CTD in of and described suggest that strong activators result in increased of pre-mRNA processing components to promoters, facilitating more processing of the transcripts that are produced. this is the it is possible that operates in a that is dependent on the pol II CTD, which has been shown previously to splicing and 3′-end cleavage to whether increased pre-mRNA processing levels dependent on a strong activator is by the CTD, we splicing and cleavage levels of the pre-mRNA by α-amanitin-resistant and of pol II, with or a CTD, and with or levels of expression of these pol II not Consistent with a S.M. Young R.A. Genes Dev. 1991; PubMed Scopus Google Scholar), levels of transcription the CTD 3, of the CTD not have a on the level of splicing or cleavage of transcripts by the resulted in a in splicing and a in cleavage that was dependent on the CTD 3, and with 5 and to This an important role for the CTD in mediating the increased splicing and cleavage levels that are dependent on a strong activator. of on whether the increased level of pre-mRNA processing observed with strong weak activators a more general of activators on pre-mRNA we the influence of transcription on the splicing of an unrelated pre-mRNA reporter, from the human which contains introns This reporter, which also has an promoter and upstream DNA binding contains an alternative and constitutive exonic from the human of the Fig. (24Cramer P. Caceres J.F. Cazalla D. Kadener S. Muro A.F. Baralle F.E. Kornblihtt A.R. Mol. Cell. 1999; 4: 251-258Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 25Kadener S. Cramer P. Nogues G. Cazalla D. de la Mata M. Fededa J.P. Werbajh S.E. Srebrow A. Kornblihtt A.R. EMBO J. 2001; 20: 5759-5768Crossref PubMed Scopus (111) Google Consistent with the results observed with the pre-mRNA transcription was by the and splicing of introns and 2 was by and with transcription was by the and activators to the was a and in splicing of introns and it is possible that the effects of activators on splicing is not an indirect consequence of effects may have on cap formation, as well as effects have on 3′-end cleavage, because 2 is most from these and 3′-end processing steps Moreover, the increased splicing levels were not an indirect consequence of expression of the activators. observed for the pre-mRNA reporter, expression of the different activators not splicing efficiency of the introns the was from a promoter DNA binding in this the promoter The results with the pre-mRNA a more and general role for activators in pre-mRNA processing levels. Our results for the a role for transcriptional activators in constitutive splicing and 3′-end cleavage levels. In we provide evidence that is a between the of a promoter-bound activator and the efficiency of constitutive splicing and 3′-end cleavage. recent studies in which the of different promoters and activators on pre-mRNA processing was in the of alternative splicing regulation (24Cramer P. Caceres J.F. Cazalla D. Kadener S. Muro A.F. Baralle F.E. Kornblihtt A.R. Mol. Cell. 1999; 4: 251-258Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 25Kadener S. Cramer P. Nogues G. Cazalla D. de la Mata M. Fededa J.P. Werbajh S.E. Srebrow A. Kornblihtt A.R. EMBO J. 2001; 20: 5759-5768Crossref PubMed Scopus (111) Google Scholar, 26Auboeuf D. Honig A. Berget S.M. O'Malley B.W. Science. 2002; 298: 416-419Crossref PubMed Scopus (313) Google Scholar, 27Nogues G. Kadener S. Cramer P. Bentley D. Kornblihtt A. J. Biol. Chem. 2002; 277: 43110-43114Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). of these studies investigated effects on the inclusion level of the in the as we have in the present study (24Cramer P. Caceres J.F. Cazalla D. Kadener S. Muro A.F. Baralle F.E. Kornblihtt A.R. Mol. Cell. 1999; 4: 251-258Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 25Kadener S. Cramer P. Nogues G. Cazalla D. de la Mata M. Fededa J.P. Werbajh S.E. Srebrow A. Kornblihtt A.R. EMBO J. 2001; 20: 5759-5768Crossref PubMed Scopus (111) Google Scholar, 27Nogues G. Kadener S. Cramer P. Bentley D. Kornblihtt A. J. Biol. Chem. 2002; 277: 43110-43114Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, J.M. J.P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Stronger promoters or activators resulted in the inclusion of the alternative S. Cramer P. Nogues G. Cazalla D. de la Mata M. Fededa J.P. Werbajh S.E. Srebrow A. Kornblihtt A.R. EMBO J. 2001; 20: 5759-5768Crossref PubMed Scopus (111) Google Scholar, 27Nogues G. Kadener S. Cramer P. Bentley D. Kornblihtt A. J. Biol. Chem. 2002; 277: 43110-43114Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). M. A. S. and B. J. This was to an of pol II G. Kadener S. Cramer P. Bentley D. Kornblihtt A. J. Biol. Chem. 2002; 277: 43110-43114Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, S. Fededa J.P. M. Kornblihtt A.R. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). In we that strong activators increased levels of splicing of the constitutive introns in this reporter, as well as the levels of splicing of the pre-mRNA activators can result in an increased level of splicing of introns for unrelated transcripts and for different constitutive introns within a Moreover, we also for the that activator can the efficiency of 3′-end processing and that this of activators can occur independently of splicing. our results provide evidence that an and possible general role for transcriptional activators is the stimulation of constitutive splicing as well as 3′-end cleavage. The splicing stimulatory property of a strong activator occurs independently of the levels of transcripts requires the CTD of pol II. is that activators result in increased pre-mRNA processing levels by pre-mRNA processing factors to pre-mRNA processing factors be recruited by activators or for association with a pol II of these factors with the pol II CTD during transcription the of splicing and 3′-end processing complexes on nascent Consistent with this have described between pre-mRNA processing factors and transcriptional activators J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), H. Y. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. P. M. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, O. Manley J.L. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), and the holoenzyme (22Robert F. Blanchette M. Maes O. Chabot B. Coulombe B. J. Biol. Chem. 2002; 277: 9302-9306Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 23Emili A. Shales M. McCracken S. Xie W. Tucker P.W. Kobayashi R. Blencowe B.J. Ingles C.J. RNA. 2002; 8: 1102-1111Crossref PubMed Scopus (146) Google Scholar). it is possible that increased splicing and cleavage levels promoted by transcriptional activators is the consequence of increased of pre-mRNA processing components to It is also to that the increased level of splicing and 3′-end cleavage may be at in to increased levels of cap formation from formation of a is known to stimulate the splicing of introns, as well as 3′-end processing of transcripts E. J. C. M. E. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar, S.M. P. E. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus (174) Google Scholar). work be at the by which activators modulate pre-mRNA processing levels. We that the efficiency of steps in including splicing, and 3′-end cleavage, is in by the of promoter-bound a mechanism may be important to the processing of increased levels of transcripts by strong transcriptional activators. We J. A. M. A. J. J. and L. for and on the D. A. D. and M. and used in these

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