Two for one: The glucocorticoid receptor as a DNA- and RNA-binding protein Open Access

Hudson, William Harris (2015)

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Glucocorticoids are a class of small molecule hormones that control inflammation, metabolism, and responses to stress in vertebrates. Due to their potent anti- inflammatory effects, glucocorticoids are prescribed for a multitude of conditions, including asthma, arthritis, organ transplant rejection, cancer, and endocrine disorders. Glucocorticoids act by binding to the intracellular glucocorticoid receptor, which is expressed in nearly all human tissue and binds to genomic DNA to control the expression of hundreds of genes. Recently, the receptor has also been shown to bind RNA, including an emerging class of cellular molecules, long intergenic non-coding RNA. This work describes the molecular mechanisms by which the glucocorticoid receptor interacts with both DNA and RNA and subsequently controls transcription of target genes. This understanding is critical not only for designing improved glucocorticoid receptor agonists but also understanding the increasing number of proteins that bind both DNA and RNA to control cellular processes such as protein expression, cell division, and genomic repair. I show that proteins that bind both RNA and DNA are numerous - approximately 2% of the human proteome - and represent an efficient mechanism of controlling important cellular processes. I then demonstrate the specific mechanisms by which such a protein - the glucocorticoid receptor - recognizes both a long non-coding RNA as well as genomic DNA elements that mediate the repression of pro-inflammatory genes. In each case, the receptor shows a capability to bind a diverse set of nucleic acid sequences in a specific manner that is evolutionarily unique from the other, related steroid receptors. Collectively, this work expands the number of human proteins known to bind both DNA and RNA and provides an in-depth analysis of how one such protein can recognize multiple nucleic substrates.

Table of Contents

List of Figures v

List of Tables viii

List of Abbreviations ix

Chapter 1: Introduction: proteins that bind DNA and RNA 1

Chapter 2: Characterization of the GR - Gas5 interaction 40

Chapter 3: Glucocorticoid-mediated transrepression 91

Chapter 4: MR DBD crystal structure 121

Chapter 5: Evolution of nGRE-mediated transrepression 143

Chapter 6: Direct repression of NF-κB 185

Chapter 7: Conclusion 218

Chapter 8: Bibliography 228

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