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MRC DiMeN Doctoral Training Partnership: A nanoscale view of replication – tackling tricky topologies to kill cancer cells


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Biochemistry Biophysics Cancer Biology Cell Biology Medical Physics Molecular Biology Nanotechnology Structural Biology

About the Project

DNA replication is essential for cell proliferation and altered processing of DNA replication structures during cancer and plays a key role in determining cell fate. DNA replication machinery has therefore become a target for therapeutic intervention – drugs that alter replication (e.g. cisplatin) are the cornerstone of cancer therapy, while drugs that inhibit cellular responses to replication stress (e.g. ATR inhibitors) are important emerging therapeutic agents. Despite therapies existing that interfere with the processing of DNA during replication and recombination, the topology of DNA at these points is poorly understood limiting therapeutic potential. This project will apply our cutting edge single-molecule Atomic Force Microscopy (AFM) techniques, capable of visualising the double helix of DNA on individual molecules, to determine the structure of previously undefined replication intermediates. AFM will allow us to explore for the first time how replicative stress induced by oncogene overexpression and therapeutics affects the structure and conformation of replication intermediates. Given the emergence of replication stress inhibitors as therapeutic agents, and the increasing awareness of the biophysical forces that act on DNA to influence cell behaviour, this project is perfectly positioned to progress our understanding of DNA stress responses with the following objectives:

1. Definitively characterise DNA topology in complex intermediate structures associated with DNA replication

2. Determine how oncogene overexpression alters the structure of DNA intermediates

3. Characterise the effect of chemotherapeutic agents on the topology of DNA intermediates and correlate this with cellular survival, replication kinetics and the DNA damage response

Together these objectives will allow for the design of novel ways to treat cancer.

You will be part of a supportive, dynamic, interdisciplinary team, spanning physicists, engineers, biologists and clinicians, using cutting edge techniques to address questions in DNA damage response and DNA repair. You will join us in our shared goal of developing better treatments for cancer patients. You will be supervised by Dr Alice Pyne with expertise in high resolution AFM of biomolecules (www.pyne-lab.uk) and Dr Helen Bryant, Head of The DNA replication and repair group (https://www.sheffield.ac.uk/medicine/people/oncology-metabolism/helen-e-bryant). You will receive training in high-resolution single-molecule imaging using AFM, and in cell biology and oncology, including the action of chemotherapeutics. You will correlate AFM findings with cellular DNA damage response assays including survival, molecular fibres (replication speed/stalling), COMET assays (DNA breaks) and immunofluorescence (repair foci and R-loops).

We collaborate internationally with academia and industry across the sciences and engineering, with downstream impact in therapeutic development. You will join a collaborative, supportive research community at Sheffield, with world-leading single molecule and nucleic acid research centres (http://www.imagine-imaginglife.com and www.genome.sheffield.ac.uk) and an active, friendly and lively PhD student cohort, which hosts regular social events alongside networking and career development opportunities. We are committed to supporting the career development of our students, encouraging attendance at both international and UK meetings, conferences and training courses to develop your research skills and interests.

As an interdisciplinary project, we welcome applicants from a diverse range of backgrounds across the physical and biological sciences and engineering. Interested applicants should contact Dr Pyne to discuss the project further (, @alicepyne).

Good luck!

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training or internships.

See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website

Studentships commence: 1st October 2021

Good luck!

References

[1] A. Pyne, R. Thompson, C. Leung, D. Roy, and B. W. Hoogenboom, ‘Single-Molecule Reconstruction of Oligonucleotide Secondary Structure by Atomic Force Microscopy’, Small, vol. 10, no. 16, pp. 3257–3261, Apr. 2014.
[2] D. King et al., MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma. Oncotarget. 2020; 11: 2141-2159.
[3] B. Klejevskaja et al., ‘Studies of G-quadruplexes formed within self-assembled DNA mini-circles’, Chem. Commun., vol. 52, no. 84, pp. 12454–12457, Jan. 2016.
[4] B. Akpinar, P. Haynes, N. Bell, K. Brunner, A. Pyne*, and B. Hoogenboom*, ‘PEGylated surfaces for the study of DNA-protein interactions by atomic force microscopy’, Nanoscale, p. 10.1039.C9NR07104K, 2019.
[5] B. Hellenkamp et al., ‘Precision and accuracy of single-molecule FRET measurements—a multi-laboratory benchmark study’, Nat. Methods, vol. 15, no. 9, pp. 669–676, Sep. 2018.

Nat Comms (2020) accepted – BioRxiv DOI: 10.1101/863423v3, Chem. Commun (2016) 52:12454, Nat Commun 11, 5863 (2020)

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