RNA machines play a pivotal role within cells yet little is known about their structures. We seek to gain a structure/function understanding of these machines at atomic detail to provide insights into human diseases associated with aberrant splicing and telomerase defects.
Non-coding RNAs play diverse cellular roles acting as messengers, regulators, structural scaffolds, and catalytic ribozymes. We use a combination of biochemistry and structural biology to understand the architecture and catalytic mechanisms of RNA molecular machines, exploring the complexity of RNA structure and the proteins that coordinate to them. The lab is currently focused on two RNA machines: the RNA splicing apparatus and the telomerase ribonucleoprotein (RNP) complex.
The spliceosome and self-splicing group II intron ribozymes share a conserved RNA core that catalyzes the RNA splicing reaction. It is estimated that at least 15% of human diseases arise from defects in splicing. A detailed understanding of the complexity within the splicing machinery is of paramount importance for developing treatments to these diseases. We aim to capture atomic resolution “snap shots” of each step along the splicing reaction, and biochemically probe the molecular interactions that drive their function.
Telomerase is a RNP that uses a RNA encoded template in coordination with a reverse transcriptase to add protective telomere DNA repeats at chromosome ends. Telomerase plays a significant role in cellular immortalization, and is therefore important for both cancer and aging. We are currently investigating the structural basis of telomerase RNP holoenzyme assembly, complex activation, and the unique mechanism of short iterative DNA repeat synthesis. Insights gained will provide a foundation for understanding the mechanisms of both inherited and acquired human diseases caused by aberrant telomerase activity.