PhD Studentship in Understanding how DNA Repair Pathway Choice is Controlled in Human Cells

Project Description:

All our cells receive thousands of DNA lesions a day, which must be repaired in an error-free way to avoid cell death and cancer. DNA double-strand breaks are the most toxic form of DNA damage and are particularly challenging for cells to repair. This is highlighted by rare human genetic disorders such as ataxia-telangiectasia and Bloom syndrome, caused by mutations in genes involved in DNA double-strand break repair which predispose patients to cancer. Furthermore, some of the most effective cancer treatments work by inducing DNA double-strand breaks in tumour cells. Future study of the cellular DNA damage response is therefore highly likely to lead to more effective cancer therapies in future.

It is still unclear how cells spatially and temporally control DNA double-strand break repair pathway choice. The aim of this project is to shed light on this issue by studying how key DNA double-strand break repair proteins are regulated by protein-protein interactions and post-translational modifications, using advanced techniques in proteomics as well as super resolution microscopy and CRISPR-Cas9 genome editing in human cells and whole organisms. We seek to answer a fundamental biological question in a clinically relevant area.

Training Opportunities:

CRISPR-Cas9 gene-editing and super-resolution microscopy, as well as basic molecular and cell biology techniques. Opportunities to gain experience in bioinformatics, proteomics and biochemistry. Students will be encouraged to present at national and international meetings, as well as regular lab meetings and journal clubs. Students will be enrolled on the MRC Weatherall Institute DPhil Course to develop basic research and presentation skills and a wide range of scientific techniques and principles to build a broadbased understanding of differing research methodologies. We hold an Athena-SWAN Silver Award in recognition of efforts to build a rewarding environment where all are supported to achieve their full potential.

Relevant Publications: Groelly, F.J., Fawkes, M., Dagg, R.A., Blackford, A.N. and Tarsounas, M., 2023. Targeting DNA damage response pathways in cancer. Nature Reviews Cancer, 23(2), pp.78-94. Shorrocks, A.M.K., Jones, S.E., Tsukada, K., Morrow, C.A., Belblidia, Z., Shen, J., Vendrell, I., Fischer, R., Kessler, B.M. and Blackford, A.N., 2021. The Bloom syndrome complex senses RPA-coated single stranded DNA to restart stalled replication forks. Nature communications, 12(1), p.585. Leimbacher, P.A., Jones, S.E., Shorrocks, A.M.K., de Marco Zompit, M., Day, M., Blaauwendraad, J., Bundschuh, D., Bonham, S., Fischer, R., Fink, D. and Kessler, B.M., 2019. MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis. Molecular cell, 74(3), pp.571-583. Blackford, A.N. and Jackson, S.P., 2017. ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Molecular cell, 66(6), pp.801-817.

Funding: This is a Cancer Research UK funded project open to UK students only.

The studentship package will cover tuition fees and contribute to living expenses.

Entry Requirements and How to Apply: first-class or strong upper second-class undergraduate degree (or predicted) in a biological, medical, mathematical or physical science or international equivalent.

Enquire: Dr Andrew Blackford andrew.blackford@oncology.ox.ac.uk

Project Link - Dept Oncology website General Enquiries: graduate.studies@oncology.ox.ac.uk

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