Prof Malcolm White
Professor
Research areas
White Lab – bacterial antiviral defence systems
CRISPR
Cells must 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 which degrade RNA or DNA 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 are also interested in developing new diagnostic tools for specific RNA detection by repurposing CRISPR effectors.
CBASS
CBASS is another prokaryotic defence system that defends against viruses using a wide range of cyclic nucleotide second messengers and effectors. CRISPR and CBASS overlap in the signals and the effectors they use, but CBASS uses a different signal generator – a nucleotide cyclase ancestral to the human cGAS innate immunity protein. In many cases it is unclear how CBASS systems sense viral infection. We are investigating the mechanism of CBASS systems and the links with cyclic nucleotide signalling more generally in bacterial cells. We are also interested in discovering the mechanisms viruses use to neutralise these defences.
PhD supervision
- Stuart McQuarrie
- Laura Gaskell-Mew
- Cooper Brown
- Yu Sun
Selected publications
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Open access
Structure of the archaeal Cascade subunit Csa5: Relating the small subunits of CRISPR effector complexes
Reeks, J. A., Graham, S., Anderson, L., Liu, H., White, M. F. & Naismith, J., May 2013, In: RNA Biology. 10, 5, p. 762-769 8 p.Research output: Contribution to journal › Article › peer-review
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Open access
Antiviral type III CRISPR signalling via conjugation of ATP and SAM
Chi, H., Hoikkala, V. P., Gruschow, S., Graham, S., Shirran, S. L. & White, M., 26 Oct 2023, In: Nature. 622, 7984, p. 826-833 22 p.Research output: Contribution to journal › Article › peer-review
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Open access
Structure of the CRISPR Interference complex CSM reveals key similarities with Cascade
Rouillon, C., Zhou, M., Zhang, J., Argyris, P., Beilsten-Edmands, V., Cannone, G., Graham, S., Robinson, C., Spagnolo, L. & White, M. F., 10 Oct 2013, In: Molecular Cell. 52, 1, p. 124-134 11 p.Research output: Contribution to journal › Article › peer-review
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Open access
Activation of Csm6 ribonuclease by cyclic nucleotide binding: in an emergency, twist to open
McQuarrie, S., Athukoralage, J. S., McMahon, S. A., Graham, S., Ackermann, K., Bode, B. E., White, M. F. & Gloster, T. M., 27 Oct 2023, In: Nucleic Acids Research. 51, 19, p. 10590-10605 16 p.Research output: Contribution to journal › Article › peer-review
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Open access
CRISPR interference: a structural perspective
Reeks, J. A., Naismith, J. & White, M. F., Jun 2013, In: Biochemical Journal. 453, 2, p. 155-166 12 p.Research output: Contribution to journal › Review article › peer-review
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Open access
Repurposing the atypical Type I-G CRISPR system for bacterial genome engineering
Shangguan, Q. & White, M., 1 Aug 2023, In: Microbiology. 169, 8, 9 p., 001373.Research output: Contribution to journal › Article › peer-review
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Iron-sulphur clusters in nucleic acid processing enzymes
White, M. F. & Dillingham, M. S., Feb 2012, In: Current Opinion in Structural Biology. 22, 1, p. 94-100 7 p.Research output: Contribution to journal › Article › peer-review
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Open access
Antiviral signalling by a cyclic nucleotide activated CRISPR protease
Rouillon, C. M. J., Schneberger, N., Chi, H., Blumenstock, K., Da Vela, S., Ackermann, K., Moecking, J., Peter, M. F., Boenigk, W., Seifert, R., Bode, B. E., Schmid-Burgk, J. L., Svergun, D., Geyer, M., White, M. & Hageluken, G., 2 Feb 2023, In: Nature. 614, p. 168–174Research output: Contribution to journal › Article › peer-review
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Open access
Displacement of the canonical single-stranded DNA-binding protein in the Thermoproteales
Paytubi, S., McMahon, S., Graham, S., Liu, H., Botting, C. H., Makarova, K. S., Kroonin, E. V., Naismith, J. & White, M. F., 14 Feb 2012, In: Proceedings of the National Academy of Sciences of the United States of America. 109, 7, p. E398-E405 8 p.Research output: Contribution to journal › Article › peer-review
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Open access
Structure and mechanism of the type I-G CRISPR effector
Shangguan, Q., Graham, S., Sundaramoorthy, R. & White, M. F., 28 Oct 2022, In: Nucleic Acids Research. 50, 19, p. 11214-11228 15 p.Research output: Contribution to journal › Article › peer-review