PhD studentship available on DNA topoisomerases. The mechanistic basis of the DNA cleavage-religation cycle of type II DNA topoisomerases – Supervisor: Prof. Tony Maxwell, Dept. Biological Chemistry, John Innes Centre, Norwich, UK
Type II topoisomerases (topos) are key enzymes involved in regulating DNA topology to facilitate essential cellular processes like DNA replication, chromosome segregation and transcription. This function is based on their ability to establish a transient DNA double-strand break and catalyse the passage of another DNA segment through the opening before religation. The break is achieved by transesterification of DNA phosphodiester bonds with tyrosine side-chains in the enzyme, catalysed by a divalent metal, generally Mg2+. Topos are unique because they efficiently combine both cleavage and ligation to allow strand passage without leaving a permanent break. Recent biochemical/structural evidence revealed that the enzyme contains two Mg2+-binding sites per DNA strand adjacent to the cleavage sites. However, the precise mechanism, its regulation by the enzyme, and its dynamics are poorly understood. Recent advances present us with the opportunity to address the mechanistic/structural questions surrounding the role of metals. The principles we derive will be applicable to many other enzymes that utilise metal ions in this way. Topos are targets for antibiotics and anti-tumour compounds, which act by stabilising the cleaved state, thereby turning the enzyme into a toxic DNA-damaging agent. Therefore, insights gained will have wide-ranging implications for drug targeting and development. The project will involve enzymological and structural studies and would be well-suited for someone with a strong background in biochemistry/chemistry and an interest in enzymology and DNA-protein interactions.
For further details see: http://students.jic.ac.uk/
Deadline for applications: 27th Nov. 2017; Contact: tony.maxwell@jic.ac.uk
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