The MMS22L–TONSL complex is a molecular "first responder" that helps cells protect and repair their DNA when it gets damaged during everyday life. In fact, when we use genome-editing to switch off this complex, cells die within one cell division. The problem is that without it, cells struggle to maintain the integrity of their genetic material—a problem at the heart of cancer, ageing, and many inherited diseases. Actually, TONSL overexpression has been linked to a range of cancers, and mutation in this gene cause debilitating symptoms. A major issue this that we don’t know how MMS22L-TONSL works at the molecular level. This state-of-the-art PhD project will explore how this complex works at the molecular level, discovering how it recognizes broken DNA, recruits repair machinery, and safeguards the stability of the genome. The project you’ll be part of is a collaboration with leading experts in genome maintenance around the world. By combining cutting-edge biochemistry, molecular biology, structural studies, and live-cell imaging, as well as genome-editing and genome-wide “-omic” technologies, the project aims to uncover new exciting insights into how cells defend themselves and how these processes can be harnessed in medicine.

References

Duro, E., Lundin, C., Ask, K., Sanchez–Pulido, Macartney, T.J., Toth, R., Ponting, C.P., Groth, A., Helleday and Rouse, J. (2010) Identification of the MMS22L–TONSL complex that promotes homologous recombination. Mol. Cell. 40, 632-644.

Saredi, G., Huang, H., Hammond, C.M., Alabert, C., Bekker-Jensen, S., Forne, I., Reveron-Gomez, N., Foster, B.M., Mlenkova, L., Bartke, T., Cejka, P., Mailand, N., Imhof, I., Patel, D.J. & Groth, A. (2016) H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex. Nature 534, 714-718