PARP inhibitors are clinical anticancer drugs that rely on trapping PARP1 at the site of a DNA break [1]. We have recently discovered that PARP also condenses damaged and undamaged DNA; that the enzyme’s co-factor NAD+ can revert this condensation for damaged DNA; and that PARP inhibitor olaparib acts to retain the DNA in a condensed conformation even in the presence of NAD+ [2].
Overall, these findings indicate a complex interplay between PARP-DNA binding, DNA extension and PARP trapping by inhibitors, and presumably their therapeutic function. To disentangle these various effects, we need to resolve PARP bound to longer DNA segments in different conformations, in different stages of PARP activation and inhibition.
In this project, we will develop and apply novel atomic force microscopy (AFM) methods to reversibly trap, visualise and study DNA in different conformations with and without bound PARP inhibitors, at nanometre resolution and in aqueous solution [3,4], with the overall aim to visualise and understand conformational changes induced by PARP binding with and without inhibitors at (sub)molecular detail.
The project is a collaboration between Prof. Bart Hoogenboom’s AFM lab (www.hoogenboom-lab.com) at the London Centre for Nanotechnology, University College London (UCL), and AstraZeneca’s BioPharmaceuticals R&D in Cambridge, UK. The student will primarily be based at UCL and will visit AstraZeneca to perform supporting experiments for a total of 3-6 months.
Student eligibility and profile: Applicants should be UK nationals or have EU settled status or indefinite leave to remain under the EU Settlement Scheme (students not meeting those criteria should provide evidence of funding to cover the difference between overseas and home tuition fees). Applicants should have or be expecting to achieve a first or upper-second class honours degree (or equivalent) in physical sciences or biology, including a clear biophysics or microscopy component. We are looking for candidates who are outstanding by their past experience in carrying out experimentally intricate research projects and by their academic performance in undergraduate and/or master level studies.
Application procedure: To apply, candidates are requested to follow the online application procedure on https://www.ucl.ac.uk/physics-astronomy/study/phd and to send a PDF copy of their application (including CV and statement of research interests) to Prof. Bart Hoogenboom ([Email Address Removed]), who will also welcome informal inquiries on this project. The application deadline is 15th February 2021, but early applications are welcome and late applications may be considered until an offer has been made and accepted.