Nick Reiter

RNA Tertiary Structure and Ribonucleoprotein Complexes That Regulate Gene Expression

Protein coding genes represent <2% of the total human genome, yet transcriptome mapping has recently revealed that at least 76% of the human genome is transcribed into RNA. Although the majority of our genome remains poorly understood, it is now clear that RNA molecules play a central role, coordinating intertwined layers of regulation that extend far beyond its role as a messenger. RNA is ideally suited to orchestrate this biological diversity because it is the only macromolecule that can both carry genetic information and perform chemical reactions by acting as an enzyme. We are at the frontier of RNA discovery and are only beginning to comprehend the 'other' 76% of the genome, how tertiary RNA structures function in biology, and how RNAs interact with macromolecular protein complexes.

Global structure and active site of the ribonuclease (RNase) P-tRNA complex. A) P RNA (blue) and protein (green) comprise bacterial RNase P and are involved in the 5' endonucleolytic cleavage of pre-tRNA (red, arrow). B) The active site region consists of two metals, a universally conserved uridine, and non-helical RNA junctions.

Whole genome approaches have exposed hundreds of transcripts with low-protein coding potential, termed long non-coding RNAs (lncRNAs), which are involved in global genome organization and maintenance. How do these lncRNAs interact with proteins to regulate gene expression? How does RNA influence the epigenetic landscape? And how does RNA processing contribute to cell-type specific expression in human cancers? As global mapping studies begin to identify these connections, there remains a dearth of knowledge at the mechanistic level. My program begins to fill this void by investigating the function and conformational dynamics of RNA-protein (RNP) complexes involved in key biological processes, from chromatin to post-transcriptional gene regulation. Our lab is particularly interested in how RNA spatially interacts with protein enzymes and how these RNAs temporally alter cellular homeostasis. To this end, we utilize structural biology tools (primarily X-ray crystallography and NMR) to decipher key interactions at the RNA-protein interface and explore how these ncRNAs can be therapeutically targeted.

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