Bespoke genetic therapies have become a reality and emerging diverse treatments are tackling the fundamental causes of many debilitating diseases. In many cases having a single amine versus a ketone or vice versa on a single DNA base can be the difference between a normal life and lifelong health challenges. We work to understand how enzymes can exchange or release amines of nucleic acid bases to help alleviate mutations linked to disease.
As primarily a wet bench biochemist, the laboratory has been focuses on understanding the biochemical mechanisms for RNA processing enzymes and how they can be used as tools for biotechnology. Bigger questions involve how transcripts are modified by numerous processing steps, coordination between organelle and nuclear genomes, and RNA/protein interactions. Currently we are investigating engineered specificity and biochemical mechanisms of C-to-U and U-to-C RNA editing tools. These RNA editing tools have a PPR tract responsible for specificity and an DYW effector domain responsible for catalysis. Questions include how to design PPR editors to have high specificity and efficiency. We address these questions through protein modeling, rational design, and experimental validation through next generation sequencing.
RNA transcripts are critical subjects of regulation since they are the informational intermediaries between DNA and protein. Mutations in DNA could theoretically be repaired at the RNA level, transcripts can be stabilized by RNA binding proteins, and transcripts can be destroyed altering the expression of proteins. Designer PPR editors can be designed to achieve each one of the actions listed above. Our laboratory has the exciting role of engineering new tools of RNA regulation to help treat disease.
C-to-U RNA editing in plants is required for photosynthetic function and is performed by a large complex with several members from various protein families. PPR proteins have been linked to C-to-U and U-to-C RNA editing, RNA maturation, splicing, RNA turnover, and translation. Since PPR proteins have such diverse functions, we are investigating how they alter transcripts. This could lead to new tools useful for the manipulation of RNAs. The world's human population is projected to grow from ~8 billion to over 11.2 billion by 2100. This will put pressure on a food production systems reliant on fossil fuels for a majority of its nitrogen. At current levels of production over-fertilization problems have led to eutrophic waters incapable of life downstream of major agricultural fields. Native RNA editing mechanisms are critical for photosynthesis and aerobic respiration in plants. Improvement of crops primary productivity through photosynthesis might allow increased crop production and reduced environmental damage in line with the Borlaug hypothesis. As CO2 levels continue to rise, plants and humans will have to adapt.