The objective of the proposed studies is to understand how a set of RNA-binding proteins regulate eucaryotic transcription elongation and termination. Our recent studies indicate that specific RNA sequence elements can direct RNA polymerase II termination in a manner that does not lead to polyadenylation of the nascent transcript. In Saccharomyces cerevisiae this mechanism is used to produce 3-ends on non-polyadenylated small nuclear and small nucleolar RNAs (snRNAs and snoRNAs). In addition, we have shown that several mRNAs are regulated by a similar mechanism. This regulatory pathway requires the function of two RNA-binding proteins, Nrd1 and Nab3, and operates through recognition of specific cis-elements in the nascent transcript. This pathway also requires the Seni RNA helicase and both the pol II CTD and a CTD kinase. The immediate objective of the proposed studies is to understand precisely how Nrd1 and Nab3 function to cause transcription termination while the longer term objective is to understand the role of the CTD and SCAFs in regulating transcription by RNA polymerase II.In this proposal our specific aims are to: (1) Define cis-elements that regulate transcription elongation through the Nrd1 -Nab3 pathway; (2) Further dissect the genetic interactions among components of the Nrd1 pathway; (3) Develop a Nrd1p-Nab3p-dependent in vitro termination assay; and (4) Characterize mammalian Nrd1-Iike proteins (SCAFs) and determine whether they play a similar role in regulating transcription termination.The ability of sequences in the nascent pol II transcript to trigger termination of non-polyadenylated transcripts is a novel regulatory mechanism. This pathway is similar to the mechanism that regulates elongation of transcripts from the HIV LTR. Similar to HIV regulation, the Nrd1-Nab3 mechanism requires the pol II CTD and a CTD kinase. Further understanding of this pathway will be important in understanding how eucaryotic genes are regulated and how these pathways may be modulated for therapeutic reasons

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National Institute of General Medical Sciences (NIGMS)
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Cell Development and Function Integrated Review Group (CDF)
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Tompkins, Laurie
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Johns Hopkins University
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Merran, Jonathan; Corden, Jeffry L (2017) Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism. Mol Cell Biol 37:
Ling, Jonathan P; Chhabra, Resham; Merran, Jonathan D et al. (2016) PTBP1 and PTBP2 Repress Nonconserved Cryptic Exons. Cell Rep 17:104-113
Corden, Jeffry L (2016) Pol II CTD Code Light. Mol Cell 61:183-4
Schaughency, Paul; Merran, Jonathan; Corden, Jeffry L (2014) Genome-wide mapping of yeast RNA polymerase II termination. PLoS Genet 10:e1004632
Kwon, Ilmin; Kato, Masato; Xiang, Siheng et al. (2013) Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. Cell 155:1049-1060
Corden, Jeffry L (2013) RNA polymerase II C-terminal domain: Tethering transcription to transcript and template. Chem Rev 113:8423-55
Darby, Miranda M; Serebreni, Leo; Pan, Xuewen et al. (2012) The Saccharomyces cerevisiae Nrd1-Nab3 transcription termination pathway acts in opposition to Ras signaling and mediates response to nutrient depletion. Mol Cell Biol 32:1762-75
Creamer, Tyler J; Darby, Miranda M; Jamonnak, Nuttara et al. (2011) Transcriptome-wide binding sites for components of the Saccharomyces cerevisiae non-poly(A) termination pathway: Nrd1, Nab3, and Sen1. PLoS Genet 7:e1002329
Corden, Jeff (2011) Going nuclear: transcribers in transit. Mol Cell 42:143-5
Jamonnak, Nuttara; Creamer, Tyler J; Darby, Miranda M et al. (2011) Yeast Nrd1, Nab3, and Sen1 transcriptome-wide binding maps suggest multiple roles in post-transcriptional RNA processing. RNA 17:2011-25

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