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An Investigation of a Role for U2 snRNP Spliceosomal Components in Regulating Transcription

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      Abstract

      There is mounting evidence to suggest that the synthesis of pre-mRNA transcripts and their subsequent splicing are coordinated events. Previous studies have implicated the mammalian spliceosomal U2 snRNP as having a novel role in stimulating transcriptional elongation in vitro through interactions with the elongation factors P-TEFb and Tat-SF1; however, the mechanism remains unknown [1]. These factors are conserved in Saccharomyces cerevisiae, a fact that suggests that a similar interaction may occur in yeast to stimulate transcriptional elongation in vivo. To address this possibility we have looked for evidence of a role for the yeast Tat-SF1 homolog, Cus2, and the U2 snRNA in regulating transcription. Specifically, we have performed a genetic analysis to look for functional interactions between Cus2 or U2 snRNA and the P-TEFb yeast homologs, the Bur1/2 and Ctk1/2/3 complexes. In addition, we have analyzed Cus2-deleted or -overexpressing cells and U2 snRNA mutant cells to determine if they show transcription-related phenotypes similar to those displayed by the P-TEFb homolog mutants. In no case have we been able to observe phenotypes consistent with a role for either spliceosomal factor in transcription elongation. Furthermore, we did not find evidence for physical interactions between the yeast U2 snRNP factors and the P-TEFb homologs. These results suggest that in vivo, S. cerevisiae do not exhibit functional or physical interactions similar to those exhibited by their mammalian counterparts in vitro. The significance of the difference between our in vivo findings and the previously published in vitro results remains unclear; however, we discuss the potential importance of other factors, including viral proteins, in mediating the mammalian interactions.

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      Most cited references 72

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      Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex.

      The yeast histone deacetylase Rpd3 can be recruited to promoters to repress transcription initiation. Biochemical, genetic, and gene-expression analyses show that Rpd3 exists in two distinct complexes. The smaller complex, Rpd3C(S), shares Sin3 and Ume1 with Rpd3C(L) but contains the unique subunits Rco1 and Eaf3. Rpd3C(S) mutants exhibit phenotypes remarkably similar to those of Set2, a histone methyltransferase associated with elongating RNA polymerase II. Chromatin immunoprecipitation and biochemical experiments indicate that the chromodomain of Eaf3 recruits Rpd3C(S) to nucleosomes methylated by Set2 on histone H3 lysine 36, leading to deacetylation of transcribed regions. This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/Bur2.
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        Progression through the RNA polymerase II CTD cycle.

        The C-terminal domain of RNA polymerase II's largest subunit undergoes dynamic phosphorylation during transcription, and the different phosphorylation patterns that predominate at each stage of transcription recruit the appropriate set of mRNA-processing and histone-modifying factors. Recent papers help to explain how the changes in CTD phosphorylation pattern are linked to the progression from initiation through elongation to termination.
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          The C-terminal domain of RNA polymerase II couples mRNA processing to transcription.

          Messenger RNA is produced by RNA polymerase II (pol II) transcription, followed by processing of the primary transcript. Transcription, splicing and cleavage-polyadenylation can occur independently in vitro, but we demonstrate here that these processes are intimately linked in vivo. We show that the carboxy-terminal domain (CTD) of the pol II large subunit is required for efficient RNA processing. Splicing, processing of the 3' end and termination of transcription downstream of the poly(A) site, are all inhibited by truncation of the CTD. We found that the cleavage-polyadenylation factors CPSF and CstF specifically bound to CTD affinity columns and copurified with pol II in a high-molecular-mass complex. Our demonstration of an association between the CTD and 3'-processing factors, considered together with reports of a similar interaction with splicing factors, suggests that an mRNA 'factory' exists which carries out coupled transcription, splicing and cleavage-polyadenylation of mRNA precursors.
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            Author and article information

            Affiliations
            Molecular Biology Section, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America
            University of Edinburgh, United Kingdom
            Author notes

            Conceived and designed the experiments: TJ SM. Performed the experiments: SM TJ. Analyzed the data: SM TJ. Contributed reagents/materials/analysis tools: TJ. Wrote the paper: TJ SM.

            [¤]

            Current address: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA)
            1932-6203
            2011
            24 January 2011
            : 6
            : 1
            3025917
            21283673
            PONE-D-10-04747
            10.1371/journal.pone.0016077
            (Editor)
            McKay, Johnson. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 11
            Categories
            Research Article
            Biology
            Biochemistry
            Nucleic Acids
            RNA
            RNA processing
            Genetics
            Gene Expression
            DNA transcription
            RNA processing
            Gene Splicing
            Model Organisms
            Yeast and Fungal Models
            Saccharomyces Cerevisiae
            Molecular Cell Biology
            Gene Expression
            DNA transcription
            RNA processing
            Nucleic Acids
            RNA
            RNA processing

            Uncategorized

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