Date of Award

Fall 12-2007

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Committee Chair

Dr. George Santangelo

Committee Chair Department

Biological Sciences

Committee Member 2

Dr. Gordon Cannon

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Dr. Yan Lin Guo

Committee Member 3 Department

Biological Sciences

Committee Member 4

Dr. Youping Deng

Committee Member 5

Dr. Anita Corbett

Abstract

Regulation o f gene transcription is a key feature of developmental, homeostatic, and oncogenic processes. The recruitment model for gene activation presumes that DNA is a platform on which the requisite components of the transcriptional machinery are assembled. In contrast to this idea, the reverse-recruitment model stipulates that the nuclear periphery is an enriched zone of pre-assembled transcriptional regulators and that target genes become active by moving to contact these peripherally anchored transcription factories. Surprisingly, many nucleoporins activate transcription themselves when fused to a heterologous DNA-binding domain. Nucleoporin activation may be a widespread eukaryotic phenomenon because it was first detected as a consequence of oncogenic rearrangements in Acute Myeloid Leukemia (AML) and related syndromes in humans. Transcriptional activation of the Rapl/G crl/G cr2 target genes occurs in association with the Nup84 subcomplex. The Rapl coactivators Gcrl and Gcr2 form an important bridge between the yeast Nuclear Pore Complex (NPC) and the transcriptional machinery. The nuclear periphery is also the site of key events in the regulation of glucose repressed genes, which together compose one-sixth of the Saccharomyces cerevisiae genome. Transcriptional activation by a subset of nucleoporins is glucose repressed and requires the Snfl/Gal83/Snf4 kinase complex for complete derepression in the absence of glucose. In the absence o f glucose, the positively acting Snfl kinase complex is activated and all three o f its subunits (a, p, and y) localize to the nuclear periphery. The glucose repressed gene SUC2, which is the best characterized target o f the Snfl kinase complex, associates tightly with the nuclear periphery when transcriptionally active but is highly mobile in the nucleoplasm when repressed. The repressor M igl is associated with components of the NPC and this association with the nuclear periphery is important for Migl to act as a repressor. Strikingly, the regulation of SUC2 is impaired when components o f the NPC and the perinuclear transcription factor Gcrl are removed. Another example of gene regulation at the nuclear periphery that I discuss is the GAL system. The activator of GAL genes, Gal4, is physically and functionally associated with the nuclear periphery. These findings allowed me to propose that the “reverse recruitment” model is likely a central feature of eukaryotic gene regulation.

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