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Inositol hexakisphosphate and Gle1P direct mRNA export by spatially regulating the dead-box protein Dbp5P at the nuclear pore complex

dc.creatorAlcazar-Roman, Abel Rodrigo
dc.description.abstractExport of mature, translationally competent messenger ribonucleoprotein particles (mRNPs) from the nucleus to the cytoplasm is a highly orchestrated process that includes transcription, capping, splicing, and 3' end formation. During these steps, the mRNP protein composition is continually altered and such remodeling is critical for proper gene expression. A striking example of mRNP remodeling occurs during mRNA export through the nuclear pore complex (NPC), the only portal for trafficking across the nuclear envelope. This study aims at deciphering the localized remodeling and release of mRNA at the cytoplasmic side of the NPC in the budding yeast Saccharomyces cerevisiae. I demonstrate that the conserved mRNA export factor Gle1 and IP6 physically interact and stimulate the RNA-dependent ATPase activity of Dbp5, a DEAD-box protein predicted to provide directionality in the mRNA export mechanism. Furthermore, I generated gle1 mutants defective in IP6 binding. In vivo and in vitro analyses of these mutants indicate that Gle1 binds IP6 in vivo, and that this binding is essential for proper mRNA export. I propose that IP6 regulates mRNA export by binding conserved basic residues within the C-terminal domain of Gle1 resembling other highly phosphorylated inositol-binding domains. Dbp5 has been shown to be recruited to mRNA as early as transcription and might accompany the mRNP through the NPC. With juxtaposed Gle1 and Dbp5 docking sites on the NPC cytoplasmic face, I propose that Gle1-IP6 activation of Dbp5 spatially controls RNP remodeling during a late mRNA export step. The GTPase activity of Ran, the regulator of protein export, is also stimulated by compartmentalized factors. Thus, localized NTPase activation may be a global mechanism for controlling the directionality of nucleocytoplasmic transport.
dc.subjectmRNA export
dc.subjectgene expression
dc.titleInositol hexakisphosphate and Gle1P direct mRNA export by spatially regulating the dead-box protein Dbp5P at the nuclear pore complex
dc.contributor.committeeMemberSusan R. Wente
dc.contributor.committeeMemberTodd R. Graham
dc.contributor.committeeMemberChristopher F.J. Hardy
dc.contributor.committeeMemberJames R. Goldenring
dc.type.materialtext and Development Biology University
dc.contributor.committeeChairDavid M. Miller, III

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