Dissecting the Molecular Biology of Cyclic Oligoadenylate Signalling

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Just like humans, bacteria have a complex immune system to protect them against infection by viruses. The CRISPR system provides adaptive immunity in bacteria, analogous to our antibody system. For the public, CRISPR is often synonymous with the Cas9 enzyme that has allowed rapid advances in genome editing technology. However, Cas9 (a type II CRISPR system) is quite rare in microbes, which more frequently have type I or type III CRISPR systems. Recently, scientists studying type III CRISPR discovered a novel signalling molecule, cyclic oligoadenylate (cOA), that is built from the main energy molecule in the cell, ATP. cOA signals an infected state in cells exposed to a virus, mobilising the cell's defences. We only know about one aspect of this defence - an enzyme that chews up RNA, called Csm6. It seems to buy the cell some time to help clear the infection, but may also cause the cell to "commit suicide" if it can't get rid of the virus. By studying the CRISPR system in different bacteria, we have discovered two new cellular defence enzymes that are activated by the cOA signal to degrade viral genetic material. We have also identified an enzyme made by viruses that rapidly breaks down cOA - it is probably acting as an "anti-CRISPR" to shut down the cell's defences. We want to understand how these three enzymes bind to cOA, how they assume an active shape and what they do, both in vitro (in the test-tube) and in vivo (in the cell). This work will provide a step change in our understanding of an important cell defence pathway. There are also potential applications in biotechnology and human health, in particular for new approaches to target drug resistant bacteria using viruses.