Gene expression is the most energetically demanding cellular process, one of the most regulated, and when uncontrolled a central feature of cancer, and human inherited genetic diseases. However, very little is known about the role of RNA in this process. The ability to diagnose, treat and prevent cancers, and other diseases, that arise from misregulation of gene expression will require a firm understanding of the relationship between RNA structure and function. Our research seeks to better understand structure-function relationships in large, non-coding RNAs by integrating data from biochemistry, spectroscopy and computational simulations. Using these three approaches we will investigate the compaction (e.g. folding landscape) and catalytic activity of a large non-coding RNA. To do this we will use a Group IIC intron from Oceanobacillus iheyensis (Oi), which is a class of self-splicing, non-coding RNA that is evolutionarily related to the spliceosome - the central machinery in human gene expression - which makes it an ideal model system.
Our specific aims will be i) to determine the thermodynamic and kinetic influences of RNA structural motifs on the compaction and catalysis of Oi, and ii) to elucidate the influence of RNA structural motifs on the conformational properties of the folding landscape of Oi. Our results will reveal how key structural motifs contribute to the folding and function of large non-coding RNA. To do this we will use mutagenesis in conjunction with biochemical experiments to show changes in the compaction and function. In addition, we'll use fluorescence resonance energy transfer (FRET) measurements in combination with computational simulations of the crystal structure from Oi to show that mutations to the RNA disturb its normal function primarily by altering the folding landscape. These results will provide new insights into the structural contributions behind RNA function and organization.

Public Health Relevance

This research seeks to discover the principles that guide the organization and assembly of large non-coding RNAs. For eukaryotes, like humans, RNA is an important component of gene expression and other important cellular functions, and is known to cause disease if damaged or defective. A better understanding of the relationship between RNA structure and function will enable us to more effectively diagnose and treat potential diseases, such as cancer, Spinal muscular atrophy and other human genetic diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04-W (20))
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Flicker, Paula F
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Yale University
Schools of Arts and Sciences
New Haven
United States
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