Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Coupling of transcription with nascent pre-mRNA metabolism

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? DESCRIPTION (provided by applicant): The production of messenger RNA (mRNA) is the primary event in gene expression where genetic information is transferred from the gene's DNA into a disposable RNA copy. Corruption of this process is a hallmark of many diseases including cancer. mRNA synthesis requires not only making an RNA transcript but maturation of that transcript by 5' capping, excision of introns and splicing of exons and 3' end formation by cleavage/polyadenylation. The mRNA is also packaged with RNA binding proteins that facilitate its maturation and ultimate export to the cytoplasm as a messenger ribonucleoprotein particle (mRNP). The mRNA processing and packaging steps that radically transform the primary transcript occur largely co-transcriptionally; that is to say the substrate of mRNA processing and packaging factors is the growing nascent RNA that is extruded by an RNA polymerase II (pol II) molecule at rates of 0.5-4.5 kilobases/min. The goal of this proposal is to understand mRNP biosynthesis in its co- transcriptional context by focusing not on the mature mRNA products but on the nascent transcripts and how their transformation is affected by the process of transcription elongation that grows RNA chains. Our working model is that synthesis and processing of a mRNA precursor are carried out in an integrated fashion within a dynamic 'mRNA factory' complex that includes both RNA polymerase and processing factors some of which make direct contacts with the pol II C-terminal domain (CTD). We use genetic and genomic approaches to ask how ongoing transcription and mRNA maturation are coupled with one another in space through recruitment of factors to the `mRNA factory' and in time through kinetic coupling mechanisms to achieve efficient and accurate production of fully formed mRNP's. In this proposal we will address these questions: 1) How does pol II transcription elongation affect processing of the nascent transcript? 2) How are nascent transcripts folded, and how is folding affected by pol II transcription elongation? 3) How does transcription elongation affect RNA binding protein association with nascent transcripts? 4) How does elongation rate affect phosphorylation of the RNA pol II CTD and recruitment of processing factors to the transcription elongation complex? 5) How does co-transcriptional RNA processing affect elongation and chromatin structure?
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