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Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 143-169). Available also in a digital version from Dissertation Abstracts.

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Thesis (Ph. D.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains v, 129 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 118-129).

Thesis (Ph. D.)--University of Texas at Austin, 2006. / Vita. Includes bibliographical references.

Thesis (Ph.D.)--Cleveland State University, 2008. / Abstract. Title from PDF t.p. (viewed on Oct. 8, 2008). Includes bibliographical references. Available online via the OhioLINK ETD Center. Also available in print.

Thesis (M.S.)--West Virginia University, 2006. / Title from document title page. Document formatted into pages; contains viii, 102 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 86-100).

Comme pour tous les autres processus en lien avec l’ADN, la structure de la chromatine lors de la transcription est dans un état de perpétuel changement. Ainsi, elle est ouverte pour permettre l’accès à l’ADN, pour ensuite se replier correctement. La dynamique de la structure chromatinienne est régulée finement par de multiples mécanismes qui agissent ensemble afin de rendre le processus hautement efficace. Ces mécanismes comprennent les modifications post-traductionelles des histones, le remodelage de la chromatine par les remodeleurs ATP-dépendants, l’incorporation des variants d’histones et l’assemblage/désassemblage des nucléosomes par les chaperons d’histones. En plus de ces activités, il y a un certain nombre de composantes non-reliées aux histones qui sont directement impliquées dans les modulations de la conformation de la chromatine associées à la transcription. Chez la levure, un de ces facteurs est la protéine HMG-like Spt2p, démontrée précédemment comme étant directement impliquée dans le réassemblage des nucléosomes dans le sillon de l’ARN polymérase II en déplacement le long du segment d’ADN transcrit. Dans la présente étude, nous démontrons que Spt2p est phosphorylée directement par la caséine kinase II (CKII) et que cette modification inhibe sa liaison à la chromatine. Nos résultats indiquent que la CKII altère l’interaction de Spt2p avec le chaperon d’histone Spt6p. Nous avons aussi trouvé que la phosphorylation directe de Spt6p par la CKII stimule l’association de ce facteur avec un autre partenaire, Iws1p. Cette association est absolument nécessaire pour le repliement correct des nucléosomes durant l’élongation. De plus, cette régulation positive du complexe Spt6p/Iws1p par la CKII module directement l’association de ce complexe avec la méthyltransférase de H3K36, Set2p. Finalement, nous avons montré que la phosphorylation de Spt6p par la CKII est essentielle à l’inhibition des promoteurs cryptiques et des erreurs de transcription. Dans l’ensemble, nos résultats suggèrent un nouveau mécanisme par lequel la CKII contrôle le repliement correct de la structure de la chromatine dans les régions codantes en modulant les interactions du chaperon d’histone essentiel Spt6p avec ses partenaires Spt2p, Iws1p et Set2p. / Like any other DNA-related process, chromatin structure is in a state of constant flux during transcription, unfolded to get access to DNA and refolded back properly. The dynamics of chromatin structure are tightly regulated and multiple mechanisms act together to make the process highly efficient. These include modifications of histones, chromatin remodeling by ATP-dependent remodeling factors, incorporation of histone variants and nucleosome disassembly and reassembly by histone chaperones. In addition to these activities, there are a number of non-histone chromatin components that are directly involved in the modulation of chromatin associated with transcription. In yeast, one of these factors is the HMG-like protein Spt2p previously shown to participate directly in the process of nucleosome reassembly in the wake of RNA polymerase II movement along transcribed DNA. In this work, we show that Spt2p is directly phosphorylated by the casein kinase II (CKII) and we demonstrate that this modification inhibits its association with chromatin. Our findings indicate that CKII disrupts the interaction of Spt2p with the histone chaperone Spt6p. Interestingly, we also found that direct phosphorylation of Spt6p by CKII stimulates the association of this factor with another partner, Iws1p. This association is absolutely required for the refolding of nucleosomes during elongation. Furthermore, this positive regulation of the Spt6p/Iws1p complex by CKII modulates directly the association of this complex with the H3K36 methyltransferase Set2p. Finally, we show that phosphorylation of Spt6p by CKII is essential to the inhibition of cryptic promoters and spurious transcription. Taken together, our results suggest a new mechanism whereby CKII directs chromatin structure refolding in coding regions by modulating the interaction of the essential histone chaperone Spt6p with its partners Spt2p, Iws1p and Set2p.

The control of extracellular adenosine is crucial to the regulation of synaptic transmission and neuroprotection. Equilibrative nucleoside transporters (ENTs) are highly expressed in the hippocampus and widely accepted as critical regulators of adenosine tone. However, the mechanisms regulating the surface distribution and transport function of ENTs are largely unknown. Since ENT1 and ENT2 contain consensus sequences for phosphorylation by protein kinase CK2, and because this protein has been reported to regulate synaptic plasticity and ENT function in non-neuronal systems, the present thesis outlines the hypothesis that CK2-induced phosphorylation of ENTs is important for their cellular localization and thus the regulation of adenosine tone and synaptic transmission. Here, a functional interaction between adenosine CK2, ENTs and AMPA receptors in the hippocampus is reported. Western blot analysis shows that a variety of CK2 inhibitors (DMAT, TBB and DRB) significantly reduced the density of ENT1 and ENT2 proteins in hippocampal membrane fractions, suggesting that CK2-mediated phosphorylation of ENTs promotes their surface localization. In contrast, it was found that the ENT1 inhibitor NBTI significantly increased in the membrane localization of ENT1, relative to the control. Moreover, ENTs were found to immunoprecipitate with GluR1 and GluR2-containing AMPA receptors; and CK2 inhibitors caused a decrease in the membrane localization of GluR2 and GluR1 AMPA receptors. These results suggest a novel signaling complex linking CK2-regulated adenosine transport to AMPA receptor trafficking in the rat hippocampus. Although the physiological significance of these findings requires further investigation, this thesis provides insight into an adenosine regulation pathway that may be important for the regulation of synaptic transmission and neuroprotection in the rat hippocampus.

The control of extracellular adenosine is crucial to the regulation of synaptic transmission and neuroprotection. Equilibrative nucleoside transporters (ENTs) are highly expressed in the hippocampus and widely accepted as critical regulators of adenosine tone. However, the mechanisms regulating the surface distribution and transport function of ENTs are largely unknown. Since ENT1 and ENT2 contain consensus sequences for phosphorylation by protein kinase CK2, and because this protein has been reported to regulate synaptic plasticity and ENT function in non-neuronal systems, the present thesis outlines the hypothesis that CK2-induced phosphorylation of ENTs is important for their cellular localization and thus the regulation of adenosine tone and synaptic transmission. Here, a functional interaction between adenosine CK2, ENTs and AMPA receptors in the hippocampus is reported. Western blot analysis shows that a variety of CK2 inhibitors (DMAT, TBB and DRB) significantly reduced the density of ENT1 and ENT2 proteins in hippocampal membrane fractions, suggesting that CK2-mediated phosphorylation of ENTs promotes their surface localization. In contrast, it was found that the ENT1 inhibitor NBTI significantly increased in the membrane localization of ENT1, relative to the control. Moreover, ENTs were found to immunoprecipitate with GluR1 and GluR2-containing AMPA receptors; and CK2 inhibitors caused a decrease in the membrane localization of GluR2 and GluR1 AMPA receptors. These results suggest a novel signaling complex linking CK2-regulated adenosine transport to AMPA receptor trafficking in the rat hippocampus. Although the physiological significance of these findings requires further investigation, this thesis provides insight into an adenosine regulation pathway that may be important for the regulation of synaptic transmission and neuroprotection in the rat hippocampus.