When cells divide it is essential that their genome is duplicated accurately and the DNA segregated correctly between the daughter cells. To achieve this, cells have developed a complex network of DNA replication and repair pathways to monitor and maintain the integrity of the genome. Failure of any of these pathways can lead to genetic instability and the development of cancer in humans.
DNA replication stress is known to drive the development and progression of most human cancers by accelerating the accumulation of the mutations that lead to cell transformation. Many tumour cells experiencing DNA replication stress become reliant on DNA damage response pathways for survival. As such, there is clinical interest in exploiting DNA replication stress therapeutically, by targeting components of the damage response and, in doing so, increasing the effectiveness of cancer treatments(1). One such potential target is PrimPol, a Y family DNA polymerase that, unusually, also possesses DNA primase activity (2). Like other Y family polymerases, PrimPol is able to replicate through a subset of DNA lesions but uniquely, is also capable of restarting stalled DNA replication forks or allowing DNA replication to initiate downstream of a lesion. While the enzymatic properties of PrimPol have been well characterised(2,3), less is known about how these activities are regulated at a molecular level. In this project a range of established biochemical, cell and molecular biology techniques, primarily using Xenopus egg extracts as a model system will be used to investigate how post-translational modifications and protein-protein interactions influence and regulate PrimPol activity during DNA replication and DNA repair. The aim of the work will be to gain insight into the mechanisms that represent potential targets for the future development of new cancer therapies.
Applications should be made directly to Dr Howard Lindsay [Email Address Removed] and should include:
CV (max 2 A4 sides), including details of two academic references
A cover letter outlining your qualifications and interest in the studentship (max 2 A4 sides)
1 Taylor, EM and Lindsay HD (2016). DNA replication stress and cancer: cause or cure?
Future Oncology Jan;12(2):221-37
2 Bianchi J, Rudd SG, Jozwiakowski SK, Bailey LJ, Soura V, Taylor E, Stevanovic I, Green AJ, Stracker TH, Lindsay HD, Doherty AJ (2013). PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication. Molecular Cell 52(4) p566-57
3 Guilliam, TA, Brissett, N.C, Ehlinger, A, Keen, B.A.,Taylor E.M. Kolesar, P., Bailey, L.J., Lindsay, H.D., Chazin, W.J. & Doherty, A.J. (2017) Molecular basis for PrimPol recruitment to replication forks by RPA Nature Communications May 23:8
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