Prof Malcolm White
Professor
Research areas
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.
PhD supervision
- Qilin Shangguan
- Remi Fritzen
- Januka Athukoralage
Selected publications
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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
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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
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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
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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
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Structure and mechanism of the CMR complex for CRISPR-Mediated antiviral immunity
Zhang, J., Rouillon, C., Kerou, M., Reeks, J., Brugger, K., Graham, S., Reimann, J., Cannone, G., Liu, H., Albers, S-V., Naismith, J. H., Spagnolo, L. & White, M. F., 10 Feb 2012, In : Molecular Cell. 45, 3, p. 303-313 11 p.Research output: Contribution to journal ? Article
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Structural and functional characterization of an archaeal clustered regularly interspaced short palindromic repeat (CRISPR)-associated complex for antiviral defense (CASCADE)
Lintner, N. G., Kerou, M., Brumfield, S. K., Graham, S., Liu, H., Naismith, J. H., Sdano, M., Peng, N., She, Q., Copie, V., Young, M. J., White, M. F. & Lawrence, C. M., 17 Jun 2011, In : Journal of Biological Chemistry. 286, 24, p. 21643-21656 14 p.Research output: Contribution to journal ? Article
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The DNA repair helicases XPD and FancJ have essential iron-sulfur domains
Rudolf, J., Makrantoni, V., Ingledew, W. J., Stark, M. J. R. & White, M. F., 15 Sep 2006, In : Molecular Cell. 23, 6, p. 801-808 8 p.Research output: Contribution to journal ? Article
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Structure of the DNA repair helicase XPD
Liu, H., Rudolf, J., Johnson, K. A., McMahon, S., Oke, M., Carter, L., McRobbie, A-M., Brown, S. E., Naismith, J. H. & White, M. F., 30 May 2008, In : Cell. 133, 5, p. 801-812 12 p.Research output: Contribution to journal ? Article
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The XBP-Bax1 Helicase-Nuclease Complex Unwinds and Cleaves DNA IMPLICATIONS FOR EUKARYAL AND ARCHAEAL NUCLEOTIDE EXCISION REPAIR
Rouillon, C. & White, M. F., 2 Apr 2010, In : Journal of Biological Chemistry. 285, 14, p. 11013-11022 10 p.Research output: Contribution to journal ? Article
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A Dimeric Rep Protein Initiates Replication of a Linear Archaeal Virus Genome: Implications for the Rep Mechanism and Viral Replication
Oke, M., Kerou, M., Liu, H., Peng, X., Garrett, R. A., Prangishvili, D., Naismith, J. H. & White, M. F., Jan 2011, In : Journal of Virology. 85, 2, p. 925-931 7 p.Research output: Contribution to journal ? Article