Human SNM1A - a novel DNA repair role and the development of inhibitors.

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Our genetic blueprint is contained within long, chromosomal complexes containing DNA present in the nucleus of our cells. However, cellular DNA is constantly under attack from reactive chemicals generated as a by-product of normal cellular function, and this damage must be repaired. Failure to repair DNA in an accurate or timely fashion is associated with a number of diseases, most prominently cancer. The DNA damage sustained by cells can, fortunately, be repaired by several complex cellular pathways, minimising changes in our DNA and thereby suppressing tumour formation.Perhaps surprisingly, however, DNA damage is induced by many anticancer treatments (chemotherapy and radiotherapy) and it is this DNA damage that is effective in killing cancer cells. In this proposal we aim to define how a specific DNA repair factor, named SNM1A, acts to repair damaged DNA. We have recently discovered that SNM1A plays an important role in the repair of breaks in the DNA double-helix, which is the clinically important form of DNA damage produced by radiotherapy and certain anticancer drugs. We will define how SNM1A promotes the repair of these double-strand breaks in both whole cells and also in biochemical studies of purified SNM1A protein. Moreover, we have recently identified several chemical compounds that can inhibit SNM1A activity in the test-tube, and aim to develop these into molecules that can enter cancer cells and inhibit SNM1A. These will be very powerful tools for further studies if SNM1A, and also might ultimately allow us to develop SNM1A inhibitor drugs that could improve patients' response to DNA damaging chemotherapy agents and radiotherapy.