Main supervisor: Dr Nigel Savery (School of Biochemistry, University of Bristol)
Second supervisor: Dr Matthew Avison (School of Cellular and Molecular Medicine, University of Bristol)
Campylobacter jejuni is one of the most prevalent foodborne pathogens for humans, estimated to affect about 1 in 100 people in developed countries each year. Food producing animals are a major source of C. jejuni, which enters the food chain via contamination of meat. When exposed to fluoroquinone antibiotics C. jejuni responds by over-producing an ATP-dependent transcription-DNA repair coupling factor called Mfd. The increased levels of Mfd confer a "mutator phenotype" on the cells, and increase the occurrence of antibiotic-resistant mutants. The pro-mutagenic effect of Mfd has been observed in response to other environmental stresses, and in other bacteria, and appears to be a general method for promoting adaptive mutagenesis (i.e. increasing the chance of a cell population acquiring mutations that will allow some fraction of the population to survive).
The ability of Mfd to increase mutation frequency is surprising, as it is best known for promoting repair of DNA damage within active genes. It is likely that this novel mechanism for adaptive mutation has its roots in the ability of Mfd to affect transcription, or in some currently unknown capacity of Mfd.
The aim of this project is to understand the mechanism and scope of Mfd-mediated adaptive mutagenesis in Campylobacter spp. The work will combine studies of mutation frequencies in native and engineered Campylobacter spp. with in vitro biochemical analysis of C. jejuni Mfd and the cellular machineries with which it interacts.
Website: http://www.bristol.ac.uk/biochemistry/research/ns.html
Funding Notes:
Competitive funding for UK/EU students via the BBSRC SWDTP is currently available for the following project:
Adaptive mutagenesis in Campylobacter spp. Dr Savery and Dr Avison
For an opportunity to undertake a SWDTP funded project with this supervisor, please visit the SWDTP website:
http://www.bristol.ac.uk/swdtp
When applying online, please ensure you include "SWDTP Funded Project" in the "Research Details" section of the online form.
References:
Howan, K., Smith, A.J., Westblade, L.F., Joly, N., Grange, W., Zorman, S., Darst, S.A., Savery, N.J. and Strick, T.R. (2012) Initiation of transcription-coupled repair characterized at single-molecule resolution. Nature, 490, 431-434.
Smith, A.J., Pernstich, C. and Savery, N.J. (2012) Multipartite control of the DNA translocase, Mfd. Nucleic Acids Res, 40, 10408-10416.
Purcell, O., di Bernardo, M., Grierson, C.S. and Savery, N.J. (2011) A multi-functional synthetic gene network: a frequency multiplier, oscillator and switch. PLoS One, 6, e16140.
Manelyte, L., Kim, Y.T., Smith, A.J., Smith, R.M., and Savery, N.J. (2010). Regulation and rate enhancement during Transcription-coupled repair. Molecular Cell. 40, 714-724.