Understanding how DNA repair pathway choice is controlled in human cells

Primary Supervisor: Dr Andrew Blackford

Second supervisor:  Dr Ross Chapman

Project Overview:

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, which are caused by mutations in genes involved in DNA double-strand break repair and 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 will be 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. In doing so, we will be attempting to answer a fundamental biological question in a clinically relevant area.

If you are interested in this project and in working in a dynamic and friendly environment, please contact Dr Andrew Blackford (andrew.blackford@oncology.ox.ac.uk) for further information.

Training Opportunities:

This DPhil project will provide training in cutting-edge techniques such as CRISPR-Cas9 gene-editing and super-resolution microscopy, as well as basic molecular and cell biology techniques. There will also be 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 also be enrolled on the MRC Weatherall Institute DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies. We also hold an Athena-SWAN Silver Award in recognition of efforts to build a happy and 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.