Cellular and Pathological Responses to Chromosome DNA Single-Strand Breaks

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My laboratory is focused on understanding how breaks in the genetic material (DNA) can lead to neurodegeneration. The proposed work will address exciting new hypotheses that have arisen during my current research Programme concerning the mechanism/s by which DNA single-strand breaks are sensed and repaired, and exciting and unexpected novel physiological roles for the pathway that repairs these breaks (single-strand break repair). We have also uncovered a mechanism by which unrepaired single-strand breaks trigger neurodegeneration, providing not only the first molecular explanation of this pathological event but also opening up possible avenues for therapeutic intervention. We plan to pursue these novel discoveries in the new Programme of work proposed here. Whilst we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work may extend to degenerative diseases observed in the normal ageing population. This is because single-strand breaks are the commonest DNA lesions arising in cells and are induced by oxidative stress; an etiological factor implicated in ageing.