. The broad objective of this proposal is to understand the mechanism of RNA polymerase II termination of both polyadenylated and non-polyadenylated transcripts. The factors and conditions that control this process play important roles in determining which genes are expressed and the level of their expression. We will continue to study the roles of Saccharomyces cerevisiae RNA-binding proteins Nrd1, Nab3 and the RNA helicase Sen1 in transcription termination. We will also investigate the roles of RNA polymerase II CTD phosphorylation and the function of a number of other RNA-binding proteins implicated in termination of both polyadenylated and non-polyadenylated transcripts. We will use a newly developed cross-linking technique to map the binding of RNA polymerase II and its termination factors to nascent RNAs in living cells. These maps and subsequent genetic and biochemical experiments will be used to: (i) identify terminator sequences that operate on different classes of RNA polymerase II transcripts and (ii) determine the mechanisms involved in removing RNA polymerase II from the template.

Public Health Relevance

. The precise point at which RNA polymerase transcription terminates can have important implications for expression of a given mRNA. In many cancers the 3'end of transcripts is different from that observed in normal cells and one of the RNA polymerase II termination factors (Sen1 or senataxin) is mutated in a spectrum of neurological disorders. Furthermore, the RNA-binding proteins that are the subject of our studies interact to form granules in stressed cells similar to granules formed by proteins involved in human neurological disorders. Thus, deeper understanding of the molecular mechanism of RNA polymerase II termination factors will advance our understanding of these human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Sledjeski, Darren D
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Johns Hopkins University
Schools of Medicine
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