Cellular and Pathological Responses to Chromosome DNA Single-Strand Breaks

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.

My laboratory is focused on understanding the molecular mechanism/s of DNA strand break repair and their links to human disease. The proposed work will address exciting new hypotheses that have arisen during my current research Programme concerning both the mechanism/s by which DNA single-strand breaks are repaired and the link between this process and neurological disease. Whilst we are focusing on experimental model systems in which single-strand break repair is defective to address these questions, the relevance of this work may extend to neurodegenerative disease 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 normal human ageing. In summary, our recent work has identified novel components of single-strand break sensing by by poly(ADP-ribose) polymerase enzymes. We have also identified new and unexpected putative roles for the single-strand break repair pathway beyond its canonical role in global genome repair that are linked to transcription and/or RNA splicing. In addition, we have identified novel gene mutations associated with single-strand break repair-defective neurodegenerative disease and uncovered a molecular mechanism by which unrepaired single-strand breaks trigger neurodegeneration; providing not only the first molecular explanation of this pathological event but also raising exciting possibilities concerning therapeutic intervention. We will now pursue the new questions and hypotheses arising from our recent work in the research Programme described here, using a combination of biochemical, cellular, and physiological model systems.

The discovery science in this Programme is firmly embedded in the MRC Strategic Research Priority Theme of "Resilience, Repair, and Replacement" and has the potential to impact on the health sector both in the short term and in the longer term. Short term benefits relate particularly to the link between unrepaired DNA single-strand breaks and neurodegeneration in cerebellar ataxias. For example, this project will address directly the hypothesis that inhibition of PARP1 activity is a putative therapeutic approach for treating neuropathologies associated with loss of single-strand break repair capacity. Although beyond the cope of the current application, since SSBs are the commonest DNA lesion arising in cells and are a cause of neurological dysfunction, it is possible that these lesions are also an etiological factor in degenerative disease in the normal (i.e. SSBR proficient) ageing population. This research might thus ultimately inform on environmental and life-style issues relating to healthy ageing in the normal population.