A Functional Interaction between the Carboxy-Terminal Domain of RNA Polymerase II and Pre-mRNA Splicing

doi:10.1083/jcb.136.1.5

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© The Rockefeller University Press, 0021-9525/1997//5 $5.00
The Journal of Cell Biology, Volume 136, Number 1, , 1997 5-18

Article

A Functional Interaction between the Carboxy-Terminal Domain of RNA Polymerase II and Pre-mRNA Splicing

Lei Du^* and Stephen L. Warren

Department of Pathology and ^* Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510

In the preceding study we found that Sm snRNPs and SerArg (SR)family proteins co-immunoprecipitate with Pol II molecules containinga hyperphosphorylated CTD (Kim et al., 1997). The associationbetween Pol IIo and splicing factors is maintained in the absenceof pre-mRNA, and the polymerase need not be transcriptionallyengaged (Kim et al., 1997). The latter findings led us to hypothesizethat a phosphorylated form of the CTD interacts with pre-mRNAsplicing components in vivo. To test this idea, a nested setof CTD-derived proteins was assayed for the ability to alterthe nuclear distribution of splicing factors, and to interferewith splicing in vivo. Proteins containing heptapeptides 1-52(CTD52), 1-32 (CTD32), 1-26 (CTD26), 1-13 (CTD13), 1-6 (CTD6),1-3 (CTD3), or 1 (CTD1) were expressed in mammalian cells.The CTD-derived proteins become phosphorylated in vivo, andaccumulate in the nucleus even though they lack a conventionalnuclear localization signal. CTD52 induces a selective reorganizationof splicing factors from discrete nuclear domains to the diffusenucleoplasm, and significantly, it blocks the accumulation of spliced, but not unspliced, human β-globin transcripts. The extent of splicing factor disruption, and the degree ofinhibition of splicing, are proportional to the number of heptapeptidesadded to the protein. The above results indicate a functionalinteraction between Pol II's CTD and pre-mRNA splicing.

Abbreviations used in this paper: CBs, coiled bodies; CTD, carboxy-terminal domain of RNA polymerase II; MIG, mitotic interchromatin granule cluster; nt, nucleotide; Pol IIa, unphosphorylated largest RNA polymerase II subunit; Pol II LS, largest subunit of RNA polymerase II; Pol IIo, hyperphosphorylated largest RNA polymerase II subunit; RT-PCR, reverse transcription-polymerase chain reaction; Sm sn RNP, Smith antigen-containing small nuclear ribonucleoprotein; SR, serine-arginine dipeptide repeat motif.

The work was supported by the Council for Tobacco Research (#3881) and National Institutes of Health (K08-CA01339) to S.L. Warren.

Please address all correspondence to S.L. Warren, Brady MemorialLaboratories, Room B117, Department of Pathology, Yale UniversitySchool of Medicine, P.O. Box 208023, New Haven, CT 06520-8023.Tel.: (203) 737-2247. Fax: (203) 785-7303. E-mail: stephen.warren{at}yale.edu

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