Structural mechanism of DNA damage response on replicating chromatin

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Every two minutes someone in the UK is diagnosed with cancer and around two thirds of these cancer patients are treated using chemotherapy and radiotherapy to kill cancer cells each year (based on Cancer Research UK statistics). These treatments aim to damage cancer cell DNA, and cause cell death. However, for some patients, these treatments are not effective, and patients develop drug/treatment resistance and cancer cells have not been effectively killed by such treatments. One of the reasons for this is that there is an internal basic mechanism in cells called the DNA damage response, which can repair DNA damage in both normal and cancerous cells, and which can enable cancer cells to escape from being killed. Two of the major aims of cancer research relating to DNA damage response mechanisms are: 1) Through understanding the mechanism of DNA damage response, we will be able to better prediction of cancer treatment outcomes by evaluating internal DNA repair abilities in patients; 2) developing new drugs to inhibit DNA repair during cancer treatment in order to overcome drug resistance and enhance the efficiency of cancer treatment. These will help to plan a much more personalised cancer treatment to make treatments more effective by targeting DDR in combination and lower doses needed for chemo/radiotherapy.My research will contribute to delivering these aims through investigating newly identified proteins called SLF1 and SLF2 involved in the DNA damage response and their interaction network in that context during DNA replication. With my expertise on DNA repair and structural biology, state-of-the-art research facilities and collaborations with other world-leading research groups at Leeds, I will firstly study the structural properties, at a molecular level, of the individual proteins and also these complexes with interaction partners. This will allow me to reveal how they bind to each other and provide important structural information for identifying the most suitable regions that can be targeted to disrupt such interactions, in the long term, by developing new cancer drugs. Secondly, I will develop protein tools that will enable me to target this complex and manipulate the assembly and function of this complex. My research will advance our current understanding of the basic mechanisms of the DNA damage response in cancer cells, which in turn underpins disease outcomes to improve the prediction of the efficacy of existing drugs, to aid in the design of new and effective personalised cancer treatments and selective tumour cell inhibitors.