Abstract #77

A new paradigm for eukaryotic gene regulation. Nayan Sarma, David Buford, Kellie Barbara, Kristine Willis, George Santangelo. Med. Biosci. & Bioinformatics, Univ. of Southern Mississippi, Hattiesburg, MS.
   It has long been suspected that nuclear substructure plays an important role in eukaryotic gene regulation. Nuclei are now known to contain a variety of distinct subcompartments, including IGCs, PML bodies, Cajal bodies, SC35 complexes, and the classically described nucleoli and nuclear pore complexes (NPCs). Each of these ultrastructural features has been implicated in various steps in gene expression, including mRNA export, splicing and transcription initiation. A plausible explanation for these findings is that in eukaryotes the nuclear position of a gene determines its transcriptional status. According to a convergent idea, that RNA polymerases are relatively immobile within the nucleus, genes are turned on or off either by attaching to a transcriptionally active proteinaceous platform or by “looping out”, respectively. What has been lacking is definitive experimental verification of a molecular model for eukaryotic gene regulation that is predicated upon the existence of nuclear ultrastructure. We recently proposed such a model, reverse recruitment, postulating that the activity of a gene is established by contact with relatively immobile transcription machines, at least some of which are tethered to NPCs. Here we show that a well-studied pathway of eukaryotic gene regulation, glucose repression in yeast cells, operates via a reverse recruitment mechanism. The canonical glucose-repressed gene SUC2 is constitutively associated with nucleoporins, and deletion of non-essential nucleoporins impairs both glucose repression and derepression on a genome-wide basis. This work also solves a long-standing puzzle regarding how the hexokinase Hxk2 participates in glucose repression—it mediates localization of the Mig1 repressor to the nuclear rim. In the absence of glucose all three subunits of the derepressing Snf1 kinase localize to the nuclear periphery, phosphorylate Mig1, and cause its export to the cytoplasm. The general features of the reverse recruitment paradigm and its potential application to most if not all eukaryotic transcriptional control mechanisms will be discussed.

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