Title

Understanding how repair of DNA double-strand breaks is controlled in human cells

Project Code: 
OIRO18AB1
Supervisor(s): 

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. Secondary supervisioon will be provided by Ross Chapman. Funding for this project will be provided through a CRUK/MRC Oxford Institute for Radiation Oncology Studentship.

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.

  1. Ochi, T. et al. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188 (2015).
  2. Balmus, G. et al. Synthetic lethality between PAXX and XLF in mammalian development. Genes Dev 30, 2152–2157 (2016).
  3. Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Molecular Cell 66, 801–817 (2017).

Students are strongly advised to contact their prospective supervisor before applying to discuss their interest in the group’s research.

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