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White, Prof Malcolm: [Group PI] Professor

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room: 307 Annexe
email: [email protected]

Defending the genome

DNA Repair

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.

CRISPR

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.source: [email protected][source: [email protected]]

Defending the genome

DNA Repair

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.

CRISPR

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.[source: Symbiosis]

Prof Malcolm White
Biomolecular Sciences Building
University of St Andrews
North Haugh
St Andrews
KY16 9ST
Fife
UK

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Athukoralage, Mr Januka: Postgraduate Student/Demonstrator

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[source: [email protected]]

My research is focused on virus-host conflict in bacteria and archaea. Almost all prokaryotes use an adaptive immune system known as CRISPR-Cas to defend against infection by viruses and phage. Guided by genetic memories of past infection, CRISPR-Cas systems detect and degrade foreign genetic material. We study the type III CRISPR-Cas system which also synthesises cyclic oligoadenylate second messengers in response to infection. Cyclic oligoadenylates stimulate additional defences in cells. Among these, cyclic oligoadenylate activated defence nucleases protect the cell by degrading RNA non-specifically, which slows down viral replication at the cost of cell growth. Uncontrolled RNA cleavage can be dangerous and potentially catastrophic, therefore off-switches are required to degrade the cyclic oligoadenylate alarm signal and deactivate defence enzymes if cells are to recover.

My work centres on mechanistic studies on cyclic oligoadenylate signalling and the discovery and characterisation of defence off-switches. Termed CRISPR ring nuclease, the cellular off-switches we have identified degrade cyclic oligoadenylates and deactivate defence enzymes to regulate the potency of the immune response.

In their battle for survival, viruses encode proteins to block CRISPR-Cas systems. These are known as Anti-CRISPRs. Remarkably, viruses have evolved their own anti-CRISPR ring nuclease variants. The anti-CRISPR ring nuclease degrades cyclic oligoadenylates much faster than the cellular counterpart and stops defence enzymes being activated. This gives viruses the upper hand; allowing them to propagate despite being detected by the cell.

The billion year war between prokaryotes and their viruses continue, and our study of their arsenals, used in offence and for defence, continue to uncover new tools that can be repurposed for biotechnology and medicine.[source: Symbiosis]

Mr Januka Athukoralage
Biomedical Sciences Building
University of St Andrews
North Haugh
St Andrews
KY16 9ST
Fife
UK

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