Investigating how cells repair DNA damage during mitosis

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.

The project aims to develop our understanding of the regulatory mechanisms controlling DNA repair pathways. Given that DNA-repair deficiencies lead to variety of health impacts including immunodeficiency, neurodegeneration and premature aging (as shown e.g. in our recent report Balmus et al., Genes Dev. 2016). The project therefore falls under the "Neurodegeneration, dementia & mental health" MRC Priority Challenge. Given the success of PARP inhibitors in targeting certain DNA repair-deficient cancers and the potential for further synthetic lethal relationships between DNA repair pathways, the project also firmly falls under the "Precision medicine" MRC Health Focus Theme.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.