Defending the genome
All organisms invest considerable resources in the maintenance, protection and repair of their genetic material, DNA. This is unsurprising, as the consequences of DNA damage can be mutation, cell death and, in humans, cancer. We utilise a variety of interdisciplinary techniques ranging from microbiology and genetics through biochemistry and molecular biology to biophysics and structural biology to study DNA repair proteins and pathways in archaea and humans.
Cells must also defend their genomes against attack by selfish genetic elements such as viruses. Although CRISPR is widely known as a genome editing technology, the CRISPR system functions as an adaptive immune system in prokaryotes. CRISPR is not synonymous with Cas9, which is an unusual type II system that is rarely present in bacteria. In contrast, type I and type III systems are much more common, and arguably much more interesting. Our lab studies type III CRISPR systems, which confer a complex, multi-layered defence against mobile genetic elements. Detection of viral RNA leads the Cas10 subunit of type III systems to generate the second messenger cyclic oligoadenylate (cOA), which sculpts the cellular response to infection. cOA activates a range of effector proteins, including the ribonuclease Csm6/Csx1, which degrades RNA non-specifically to slow down both viral and host metabolism and “buy some time”. We recently identified and characterised a “Ring nuclease” enzyme, which degrades the cOA signal and returns cells to an uninfected state following viral RNA clearance. Predictably, viruses have evolved countermeasures known as anti-CRISPRs, and we recently discovered a viral anti-CRISPR that circumvents type III CRISPR immunity by rapidly degrades the cOA signalling molecule.
We have been funded by the BBSRC, Cancer Research UK, Association for International Cancer Research, Royal Society, EU framework VII and the Wellcome Trust.
Enquiries from potential Masters and PhD students are welcome at any time.
A short cv is available here: cv 2019 short
Group photo from the 2013 CRISPR Conference in St Andrews: