Every day, tens of thousands of single-strand breaks occur in the DNA inside each of our cells, and when the repair of these breaks fails, the nervous system begins to degenerate. This research programme addresses a critical gap in knowledge: while the link between DNA breaks and cancer is well understood, the causal chain from a single-strand break to neurodegeneration—in both rare hereditary diseases and normal ageing—remains largely unknown. The team will investigate the repair protein XRCC1, whose loss triggers premature ageing hallmarks in the brain, and explore newly discovered molecular links to the neurodegenerative disease ataxia oculomotor apraxia-2. This is fundamental science. It does not promise a treatment tomorrow. But understanding how the brain’s most common form of DNA damage drives degeneration could eventually open new avenues for managing diseases—from inherited neurological conditions to the cognitive decline that accompanies ageing—by targeting the repair process itself.
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Breaks in the genetic material (DNA) can lead to a variety of hereditary and age-related diseases, including cancer and neurodegeneration. Whilst the causal link between DNA breaks and cancer is quite well understood, the causal link between DNA breaks and degeneration of the nervous system is not. The aim of the proposed programme is to address critical unanswered questions and new hypotheses concerning the mechanism/s by which breaks in a single strand of DNA (DNA single-strand breaks) are repaired, and the link between this process and degenerative disease. Understanding how DNA single-strand breaks can cause neurodegeneration is important not only for understanding hereditary diseases associated with neurological dysfunction (and hopefully in future for treating and managing such diseases), but most likely also for understanding degenerative diseases associated with normal ageing. This is because DNA single-strand breaks are the commonest lesions arising in cells and are a product of oxidative stress, which in turn is a major etiological factor in pathologies associated with ageing. Indeed, our recent experiments reveal that loss of the critical DNA single-strand break repair protein XRCC1 results in premature onset of molecular and pathological hallmarks of ageing and, moreover, that un-repaired DNA damage in the brain can trigger these hallmarks, systemically (i.e. in undamaged tissues). In addition, we have identified molecular links between the DNA damage response and the hereditary neurodegenerative disease ataxia oculomotor apraxia-2, which we propose identifies a new component of the cellular control of gene expression in the presence of DNA lesions and can explain the basis of this disease. We will now pursue our recent novel findings and hypotheses in this research Programme. In particular, we will address critical questions concerning the organisation and importance of DNA single-strand break repair in vivo, focussing on a novel unidentified role for XRCC1 and on the mechanism by which this protein is recruited at single-strand breaks, and on how DNA single-strand break repair impacts on hereditary and ageing-related degenerative disease. Ultimately, we envisage this work will identify new avenues for treatment & management of degenerative diseases that are associated, wholly or partly, with DNA breakage.
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