The projects in the Toor lab focus on the structure and function of non-coding regions of prokaryotic and eukaryotic genomes. Two genetic elements particularly abundant in these organisms are introns and retroelements. For example, ~50% of the human genome consists of spliceosomal introns and non-LTR retroelements. Both of these are considered to have evolved from a class of introns which originated in bacteria billions of years ago called the group II introns. Group II introns share many structural and/or biochemical features with the spliceosome and non-LTR retroelements. We have solved the first crystals structure of an intron lariat. In addition, we solved cryo-em structures of the group II intron invading a DNA substrate.
There is now extensive evidence to support the hypothesis that group II introns are ancestral to the spliceosome. It has been hypothesized that eukaryogenesis was initiated through intron invasion of the archaeal host genome. This model proposes that bacterial group II introns invaded the pre-eukaryotic genome, forming the predecessors of spliceosomal introns. The resulting necessity to spatially separate RNA splicing from protein translation then induced eukaryogenesis through the evolution of the nuclear membrane. To evaluate the validity of this model, we are investigating the evolution and structures of group II intron pre-spliceosomal complexes that are thought to have directly preceded eukaryogenesis.
Recently, there has been great success and interest in the use of RNA as a therapeutic for many different human diseases. Some of these RNA therapeutics have been FDA-approved and many others are currently in clinical trials. The common thread underlying all of these approaches has been the use of RNA that has been chemically modified for a significantly greater half-life and in vivo stability. Unmodified RNA is highly unstable and degrades in the human body within a matter of hours. We use organic chemistry to develop tools to enable unlimited chemical diversification of RNA for additional functionality and stability.
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