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Articles 1 - 11 of 11
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Role Of P300 Zz Domain In Chromatin Association And Histone Acetylation, Yongming Xue
Role Of P300 Zz Domain In Chromatin Association And Histone Acetylation, Yongming Xue
Dissertations & Theses (Open Access)
Transcription is strictly regulated by numerous factors including transcription coactivators. The p300 protein and its close paralogue CREB-binding protein (CREBBP, aka CBP) are well-known transcriptional coactivators that have intrinsic lysine acetyltransferase activity. The functions of p300/CBP largely rely on their capabilities to bind to chromatin and to acetylate the histone substrates. However, the molecular mechanisms underlying the regulation of these processes are not fully understood.
Through combination of various biochemical, biophysical and molecular approaches, we show that the ZZ-type zinc finger (ZZ) domain of p300 functions as a histone reader that specifically binds the N-terminal tail of histone H3. Crystal …
A Role For Epac1 And Epac2 In Nociceptor Hyperexcitability And Chronic Pain After Spinal Cord Injury, Samantha Berkey
A Role For Epac1 And Epac2 In Nociceptor Hyperexcitability And Chronic Pain After Spinal Cord Injury, Samantha Berkey
Dissertations & Theses (Open Access)
Chronic pain is a major complaint of those living with spinal cord injury (SCI), affecting 65-80% of the SCI population, but the treatment options remain limited or non-existent. The cAMP sensor EPAC has previously been shown to play a key role in chronic inflammatory and neuropathic pain, though the contribution from each of its two main isoforms, EPAC1 and EPAC2, is unclear. Here I test the hypothesis that both EPAC1 and EPAC2 play a key role in the maintenance of persistent nociceptor hyperexcitability and chronic pain after SCI.
Using both a T9 SCI mouse model and a T10 SCI rat …
Characterizing The Recognition Motif And Novel Substrates Of Carm1, Sitaram Gayatri
Characterizing The Recognition Motif And Novel Substrates Of Carm1, Sitaram Gayatri
Dissertations & Theses (Open Access)
A limited pool of proteins attains vast functional repertoire due to posttranslational modifications (PTMs). Arginine methylation is a common posttranslational modification, which is catalyzed by a family of nine protein arginine methyltransferases or PRMTs. These enzymes deposit one or two methyl groups to the nitrogen atoms of arginine side-chains. Elucidating the substrate specificity of each PRMT will promote a better understanding of which signaling networks these enzymes contribute to. Although many PRMT substrates have been identified, and their methylation sites mapped, the optimal target motif for each of the nine PRMTs has not been systematically addressed. Here we describe the …
Functional Similarity Of Prd-Containing Virulence Regulators In Bacillus Anthracis, Malik Raynor
Functional Similarity Of Prd-Containing Virulence Regulators In Bacillus Anthracis, Malik Raynor
Dissertations & Theses (Open Access)
Bacillus anthracis produces three regulators, AtxA, AcpA, and AcpB, that control virulence gene expression and are members of an emerging class of regulators termed “PCVRs” (Phosphoenolpyruvate-dependent phosphotransferase regulation Domain-Containing Virulence Regulators). AtxA controls expression of the toxin genes; lef, cya, and pag, and is the master virulence regulator and archetype PCVR. AcpA and AcpB are less well studied. AcpA and AcpB independently positively control transcription of the capsule biosynthetic operon capBCADE, and culture conditions that enhance AtxA activity result in capBCADE transcription in strains lacking acpA and acpB. RNA-Seq was used to assess the regulons of the …
The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland
The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland
Dissertations & Theses (Open Access)
DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is …
Nanoscale Organization Of The Small Gtpase Rac1, Kelsey Maxwell
Nanoscale Organization Of The Small Gtpase Rac1, Kelsey Maxwell
Dissertations & Theses (Open Access)
Rac1 is a small, guanine-nucleotide binding protein that cycles between an inactive GDP-bound and active GTP-bound state to regulate actin-mediated motility, migration, and adhesion. Plasma membrane (PM) localization is essential for its biological activity. Rac1 PM targeting is directed by a C-terminal membrane anchor that encompasses a geranylgeranyl-cysteine-methyl-ester, palmitoyl, and a polybasic domain (PBD) of contiguous lysine and arginine residues. Using high-resolution imaging combined with spatial mapping analysis, I found that Rac1 forms nanoclusters on the PM. Cycling between the GTP- and GDP-bound states, Rac1 forms nanoclusters that are non-overlapping, consequently undergoing guanine nucleotide-dependent spatial segregation. I further found that …
Deciphering The Roles Of Δnp63 In Regulating Epithelial To Mesenchymal Transition, Cancer Progression And Metastasis, Ngoc Bui
Dissertations & Theses (Open Access)
p63 is a member of the p53 family, a well-known tumor suppressor which is considered the guardian of the genome. The TP63 gene encodes multiple isoforms that can be categorized into two main isoforms, TAp63 and ΔNp63, which are expressed in different cellular compartments and have distinct functions in many biological processes. While the Flores laboratory identified TAp63 as a tumor and metastasis suppressor, the precise roles of ΔNp63 isoforms in tumorigenesis and metastasis remain elusive. ΔNp63 is the predominant p63 isoform expressed in the epidermis and plays essential roles in regulating epidermal development and homeostasis. Utilizing a ΔNp63-conditional …
Biological Clocks, Inflammation, And Multiorgan Damage In Sickle Cell Disease, Morayo Adebiyi
Biological Clocks, Inflammation, And Multiorgan Damage In Sickle Cell Disease, Morayo Adebiyi
Dissertations & Theses (Open Access)
Sickle cell disease (SCD) is a dangerous condition caused by a genetic mutation on the human beta-globin gene that contributes to erythrocyte sickling, the hallmark of the disease. Previous metabolomics studies have confirmed that elevated sphingosine kinase 1 (SphK1) mediates sphingosine-1-phosphate (S1P) production to promote erythrocyte sickling. S1P signals via five S1P receptors (S1PR) regulates several pathophysiological functions.
In the first chapter of this dissertation, I explored the role of S1PRs in SCD by utilizing pharmacologic and genetic tools. To determine the role of S1P-S1PRs signaling in SCD, I treated humanized Berkeley sickle mice (Berkeley HBS mice), with FTY720, a …
Investigating The Impact Of Intragenic Dna Methylation On Gene Expression, And The Clinical Implications On Tumor Cells And Associated Stroma, Michael Mcguire
Investigating The Impact Of Intragenic Dna Methylation On Gene Expression, And The Clinical Implications On Tumor Cells And Associated Stroma, Michael Mcguire
Dissertations & Theses (Open Access)
Investigations into the function of non-promoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated non-promoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we uncovered an enrichment of DNA methylation sites within the gene body and 3’UTR in which DNA methylation is strongly positively correlated with gene expression. We examined 32 tumor types and identified 57 …
Evolution Via Gene Duplication And Alternative Splicing In The Eukaryotic Ski7 And Hbs1 Genes, Alexandra Marshall
Evolution Via Gene Duplication And Alternative Splicing In The Eukaryotic Ski7 And Hbs1 Genes, Alexandra Marshall
Dissertations & Theses (Open Access)
Gene duplication and alternative splicing are both recognized as important drivers of proteomic diversity and innovation during evolution, but the evolutionary changes over long periods of time or the interrelations of the two processes has not been extensively studied. Here I study these phenomena for the SKI7 and HBS1 gene pair. These Saccharomyces cerevisiae genes were created as part of a whole genome duplication (WGD) event and have since functionally diverged. Although both genes function in mRNA surveillance pathways, the two genes act on different RNAs and have different effects on the target mRNAs. Ski7 brings the Ski complex and …
Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow
Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow
Dissertations & Theses (Open Access)
Skp2 (S-phase kinase-associated protein 2), one component of the SCF E3 ubiquitin ligase complex, directly interacts with Skp1 and indirectly associates with Cullin1 and Rbx1 to bridge the E2 conjugating enzyme with its protein substrate to execute its E3 ligase activity. Skp2 is an Fbox protein (due to it containing an Fbox domain) and it is the rate-limiting component of the SCF complex. Skp2 targets several cell-cycle regulatory proteins for ubiquitination and degradation; most notable and significant for cancer are the cyclin-dependent kinase inhibitor, p27. Skp2 is an oncogene and studies have shown that over-expression of Skp2 leads to increased …