DNA damage poses a serious threat to proper chromosome segregation during cell division, and if repaired incorrectly can cause cell death or cancer. Paradoxically, during mitosis, dividing cells switch off DNA repair pathways until their daughter cells re-enter interphase. Therefore, how cells deal with DNA damage that occurs during mitosis is still unclear, but this is a critical question in basic cancer cell biology because many cancer therapies including radiotherapy and some chemotherapeutic drugs cause DNA damage that kills cancer cells during mitosis.
We recently identified a novel protein complex with a specific role in the cellular response to DNA damage during mitosis. This complex marks DNA breaks and forms protein filaments that can bridge two broken DNA ends. However, we still do not understand how this protein complex forms, how it is regulated, and what the consequences are for organisms that lack it.
The aim of this DPhil project is to address these questions and in doing so, provide novel insights into a novel fundamental biochemical pathway that could be targeted as a novel anti-cancer therapy.
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.
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. 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).
3. Leimbacher, P. et al. MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis. Molecular Cell 74, 571-583 (2019).
If you are interested in this project and in working in a dynamic and friendly environment, please contact Dr Andrew Blackford ([email protected]
) for further information.