Chromosomal Single-Strand Break Repair: Mechanisms and Degenerative Disease

遗传物质(DNA)的断裂可能会导致各种遗传性和与年龄相关的疾病，包括癌症和神经退化。虽然DNA断裂和癌症之间的因果联系已经被很好地理解了，但DNA断裂和神经系统退化之间的因果联系还不是很清楚。拟议方案的目的是解决有关修复单链DNA断裂(DNA单链断裂)的机制以及这一过程与退行性疾病之间的联系的关键悬而未决的问题和新的假设。了解DNA单链断裂如何导致神经退化不仅对于理解与神经功能障碍相关的遗传性疾病(有望在未来治疗和管理此类疾病)很重要，而且很可能对于理解与正常衰老相关的退行性疾病也很重要。这是因为DNA单链断裂是细胞中最常见的损伤，是氧化应激的产物，而氧化应激又是与衰老相关的病理中的一个主要病因。事实上，我们最近的实验表明，关键的DNA单链断裂修复蛋白XRCC1的丢失会导致衰老的分子和病理特征的过早出现，而且，大脑中未修复的DNA损伤可以系统性地(即在未受损的组织中)触发这些特征。此外，我们还发现了DNA损伤反应与遗传性神经退行性疾病共济失调动眼失用症-2之间的分子联系，我们认为这发现了DNA损伤存在时细胞控制基因表达的新成分，并可以解释这种疾病的基础。我们现在将在这个研究计划中继续我们最近的新发现和假设。特别是，我们将解决关于体内DNA单链断裂修复的组织和重要性的关键问题，重点是XRCC1的一个新的未知角色和该蛋白在单链断裂中被招募的机制，以及DNA单链断裂修复如何影响遗传性和衰老相关的退行性疾病。最终，我们预计这项工作将确定治疗和管理退行性疾病的新途径，这些疾病完全或部分与DNA断裂有关。

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.