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The drugs don’t work: Developing a combined magnetic tweezers and TIRF-FRET platform to investigate the mechanopharmacology of DNA repair inhibitors.


Department of Oncology and Metabolism

Dr C Toseland , Dr T Craggs Wednesday, May 19, 2021 Competition Funded PhD Project (Students Worldwide)
Sheffield United Kingdom Biochemistry Biophysics Cancer Biology Molecular Biology

About the Project

About the Project

This studentship is available to develop and apply state-of-the-art single molecule imaging and manipulation techniques to study the molecular basis of DNA Repair.

DNA-protein interactions underpin essential cellular processes such as DNA replication, transcription, and repair, and proteins involved in these processes are targeted in a variety of cancer therapies. Many structures of damaged DNA-protein complexes reveal stark bends in the DNA substrate, suggesting that proteins may exert force on the DNA to bend it during recognition of the damage site, or for catalytic enhancement of the repair.

Here you will develop novel instrumentation to investigate how force modulates the DNA-protein interactions involved in DNA repair, and establish high-throughput screening methods which mimic physiological forces on DNA substrates. These forces naturally arise in cells due to transcription and DNA packaging, and will improve hit identification for repair inhibitors, advancing the emerging field of mechanopharmacology.

Objectives:

(1) Design and build a combined magnetic tweezer-single molecule fluorescence microscope in collaboration with Cairn Research.

(2) Use the new instrument to investigate the effect of forces on DNA-protein interactions and DNA damage recognition.

(3) Implement a high-throughput version of the assay to screen protein-DNA interactions under physiological forces.

You will be part of a new multidisciplinary collaboration between Dr. Tim Craggs (Dept. of Chemistry http://www.craggs-lab.com), Dr. Chris Toseland (Dept. of Oncology and Metabolism http://www.toseland-lab.com) and Cairn Research (www.cairn-research.co.uk). You will receive excellent training in developing novel instruments and assays to study DNA-protein interactions, whilst working directly with instrument engineers.

You will join a collaborative, supportive research community in Sheffield, with world-leading single molecule and nucleic acid research centres (http://www.imagine-imaginglife.com and http://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 conferences and training courses to develop your research skills and interests.

Given the interdisciplinary nature of the role, we encourage applications from a diverse range of scientific backgrounds e.g. biophysics, physics, and biochemistry. Motivated individuals from all backgrounds will receive all the necessary training to excel in this project.

Entry Requirements:

Candidates must have a first or upper second class honors degree with a background in biophysics, biochemistry, physics or a related discipline.

How to apply:

Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select 'Oncology & Metabolism' as the department. Please also state your first and second choice project by entering the project tiles in the 'Research Topic' box on your application.

 

Enquiries:

Interested candidates should in the first instance contact Dr Chris Toseland -


Funding Notes

This studentship will be 42 months in duration and include home fee and stipend at UKRI rate. EU/Overseas candidates are welcome to apply, however they would be required to fund the fee difference.

References

Nat Commun 11, 5641 (2020). https://doi.org/10.1038/s41467-020-19468-4
Nuc Acids Res (2019) 47:10788
Nat Methods (2018) 15: 669
Nuc Acids Res (2021) 49 340-353
Biophys. J (2021) 120 631-641


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