Various human genetic diseases are caused by defects in the DNA-damage response (DDR). DDR genes protect against cancer, as demonstrated by their somatic mutation or epigenetic silencing being common in cancers. Cancer-specific DDR deregulation is ripe for therapeutic exploitation but clinicians are facing two main problems: accurate identification of such exploitable cancer cell defects and development of resistance mechanisms that render tumours unresponsive to classical or targeted chemotherapies. A promising concept to address these issues is “synthetic viability”, wherein a combination of gene defects rescues the lethal effects of a single gene change. Recent work in model systems has highlighted the strong potential for synthetic viability screening to identify and understand relationships between DDR (and other) cellular components, thereby providing insights relevant to understanding and treating cancer. Furthermore, such screening approaches could also provide insights into, and suggest new treatment paradigms for, various human genetic diseases. The key objective of this Marie Curie project proposal is to explore synthetic viability principles applied to DDR mechanisms. I will carry out synthetic viability screens for genes whose mutation/loss suppresses cellular defects caused by loss of key DDR proteins. I will then carry out studies to determine whether such suppressors could be exploited as potential targets whose inhibition would alleviate the corresponding hereditary genetic disease, or whose re-activation might selectively re-sensitise cancers to DNA damage or DDR inhibitors. This work should thus not only provide insights into DDR processes and interactions between them, but could also suggest avenues for developing newer and more effective personalized cancer treatments. These studies might also suggest new treatment regimens for human DDR deficiency syndromes, and could provide a platform more broadly applicable to many inherited human diseases.
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