Professor Carl Smythe
We have a long-standing interest in understanding cellular surveillance mechanisms, determining the consequences when they fail, and utilizing this information to inform the process of drug development, including the exploration of novel chemical space. Surveillance mechanisms include aspects of regulation of cell cycle progression and the DNA damage response, the regulation of mRNA quality control, DNA replication and telomere stability. In 1989, we were one of the first groups to demonstrate the principle of chemical synthetic lethality as a potential novel therapeutic principle, showing that caffeine uncoupled the dependence of mitosis on the completion of S-phase. We were the first group to show that Chk1 activation failure is the consequence of caffeine treatment and that ATR is the direct target of caffeine.
We use a multi-disciplinary approach, collaborating with colleagues in all of the sciences, combining cell and molecular biology techniques with high-throughput genomics and proteomics to provide mechanistic insight into surveillance systems. Current research interests include the checkpoint that couples DNA replication to the regulation of histone mRNA supply, the modulation of nonsense-mediated decay of mRNA, and the mechanism by which the RNA/DNA helicase Upf1 is recruited to chromatin to ensure telomere integrity. We have undertaken a genome-wide siRNA screen to search for novel genes involved in the checkpoint coupling replication with the onset of mitosis, and are undertaking analysis of 4 previously unidentified genes that act on this pathway.
We have a number of collaborative projects with other centre members. These include i) a long-standing collaboration with Jim Thomas on the exploitation of Ru(II) based organo-metallic systems for the identification of next generation theranostics for platinum-resistant tumours, ii) the mechanism of action of Upf1 with Cyril Sanders, and the role of phosphorylation in the regulation of Fen1 function with Jane Grasby.
- Walker, M.G., P.J. Jarman, M.R. Gill, X. Tian, H. Ahmad, P.A. Reddy, L. McKenzie, J.A. Weinstein, A.J. Meijer, G. Battaglia, C.G. Smythe, and J.A. Thomas. 2016. A Self-Assembled Metallomacrocycle Singlet Oxygen Sensitizer for Photodynamic Therapy. Chemistry. 22:5996-6000.
- Gotham, V.J., M.C. Hobbs, R. Burgin, D. Turton, C. Smythe, and I. Coldham. 2016. Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. Organic & biomolecular chemistry. 14:1559-1563.
- Ramu, V., M.R. Gill, A. Das, P. Jarman, D. Turton, J.A. Thomas, and C. Smythe. 2015. A cytostatic ruthenium(II)-platinum(II) bis(terpyridyl) anticancer complex that blocks entry into S phase by up-regulating p27KIP1. Chemistry. in press.
- Novodvorsky, P., O. Watson, C. Gray, R.N. Wilkinson, S. Reeve, C. Smythe, R. Beniston, K. Plant, R. Maguire, M.K.R. A, S. Elworthy, F.J. van Eeden, and T.J. Chico. 2015. klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. PloS one. 10:e0141611.
- Wragg, A., M.R. Gill, C.J. Hill, X. Su, A.J. Meijer, C. Smythe, and J.A. Thomas. 2014a. Dinuclear osmium(II) probes for high-resolution visualisation of cellular DNA structure using electron microscopy. Chemical communications. 50:14494-14497.
- Wragg, A., M.R. Gill, D. Turton, H. Adams, T.M. Roseveare, C. Smythe, X. Su, and J.A. Thomas. 2014b. Tuning the cellular uptake properties of luminescent heterobimetallic iridium(III)-ruthenium(II) DNA imaging probes. Chemistry. 20:14004-14011
- Baggaley, E., M.R. Gill, N.H. Green, D. Turton, I.V. Sazanovich, S.W. Botchway, C. Smythe, J.W. Haycock, J.A. Weinstein, and J.A. Thomas. 2014. Dinuclear ruthenium(II) complexes as two-photon, time-resolved emission microscopy probes for cellular DNA. Angewandte Chemie. 53:3367-3371.
- Bishop, A., R. Lane, R. Beniston, B. Chapa-y-Lazo, C. Smythe, and P. Sudbery. 2010. Hyphal growth in Candida albicans requires the phosphorylation of Sec2 by the Cdc28-Ccn1/Hgc1 kinase. The EMBO journal. 29:2930-2942.
- Gill, M.R., J. Garcia-Lara, S.J. Foster, C. Smythe, G. Battaglia, and J.A. Thomas. 2009. A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. Nature chemistry. 1:662-667
- Muller, B., J. Blackburn, C. Feijoo, X. Zhao, and C. Smythe. 2007. DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. The Journal of cell biology. 179:1385-1398.
- Feijoo, C., C. Hall-Jackson, R. Wu, D. Jenkins, J. Leitch, D.M. Gilbert, and C. Smythe. 2001. Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. The Journal of cell biology. 154:913-923.
- Smythe, C., and J.W. Newport. 1992. Coupling of mitosis to the completion of S phase in Xenopus occurs via modulation of the tyrosine kinase that phosphorylates p34cdc2. Cell. 68:787-797.