CRISPR is a prokaryotic adaptive immune system that has been harnessed for a wide range of genome engineering, synthetic biology, biotechnology and healthcare applications. This project will focus on the CRISPR system of the important human pathogen Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb has a Type III CRISPR system which is more complex than Cas9, consisting of a large ribonucleoprotein machine that detects tiny amounts of viral RNA and unleashes an array of defensive enzymes that target and degrade invading genetic entities (1,2). Although this is a powerful immune defence, it must be tightly controlled to avoid killing the host. Many aspects of the Type III CRISPR system remain to be discovered.
In this project, you will focus on the Type III Mtb CRISPR system, which we have expressed and purified for the first time. The overall aim will be to develop an understanding of the activities and control of the system that allows it to provide host immunity. For example, we wish to understand how binding of a viral RNA changes the structure of the ribonucleoprotein machine and activates the catalytic domains. This will involve a collaboration between the White and Penedo labs in Biology and Physics, and will provide opportunities for training in a wide range of cutting-edge technologies including molecular biology, synthetic biology and single molecule biophysics. In parallel, there are opportunities to manipulate the genome of Mtb using its own CRISPR system, to advance studies of this important pathogen.
You will join a well-funded and friendly lab occupying new, purpose-built lab space in the Biomedical Sciences Research Complex at St Andrews. For more information or informal enquiries, please contact Prof Malcolm White (email@example.com) or Dr Carlos Penedo (firstname.lastname@example.org).
Athukoralage, J. S., Rouillon, C., Graham, S., Grüschow, S., & White, M. F. (2018). Ring nucleases deactivate Type III CRISPR ribonucleases by degrading cyclic oligoadenylate. BioRxiv, 380436. doi:https://doi.org/10.1101/380436 (in press at Nature).
Rouillon, C., Athukoralage, J. S., Graham, S., Grüschow, S., & White, M. F. (2018). Control of cyclic oligoadenylate synthesis in a type III CRISPR system. Elife, 7, e36734.
To apply for this project, please go to this link.