Understanding how DNA repair pathway choice is regulated in human disease
Supervisor: Dr Andrew Blackford
Every cell in our bodies receives thousands of DNA lesions a day, which must be repaired in an error-free way to avoid genome instability, 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 DNA double-strand break repair genes and cause developmental defects, immunodeficiency, premature aging and cancer. Furthermore, some of the most effective cancer treatments work by inducing DNA double-strand breaks in tumour cells. Future study of the DNA damage response is therefore highly likely to lead to more effective cancer therapies in future.
DNA double-strand breaks are primarily repaired by two pathways in human cells: non-homologous end-joining and homologous recombination. It is crucial that cells are able to use the right repair pathway in the proper context, as inappropriate pathway choice is a primary cause of genome instability and tumourigenesis via mechanisms such as chromosomal translocations and loss-of-heterozygosity. However, exactly how cells regulate DNA repair pathway choice is still unknown.
The aim of this project will be to shed light on this issue by exploiting recent advances in molecular phylogenetics, proteomics and genome editing to identify and characterize functionally important protein-protein interactions and post-translational modifications in DNA repair pathways in human cells—concentrating in particular on those that define repair pathway choice. 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 young, dynamic and friendly environment, please contact Dr Andrew Blackford (firstname.lastname@example.org) for further information.
Training opportunities: This project will involve training in standard molecular and cell biology techniques, as well as cutting edge CRISPR-Cas9 genome editing, super-resolution microscopy and proteomics. There will also be opportunities to gain experience in biochemistry, structural biology and mouse models via our collaborators. Students will be encouraged to attend and present their work at national and international meetings, and to be involved in organizing and presenting at journal clubs and departmental seminar series.References
- Jackson SP & Helleday T (2016) Drugging DNA repair. Science 352, 1178–1179.
- Blackford AN & Jackson SP (2017) ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801-817.
- Balmus G et al. (2016) Synthetic lethality between PAXX and XLF in mammalian development. Genes Dev. 30, 2152-2157.
- Ochi T, Blackford AN et al. (2015) PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347, 185–188.