Molecular Characterisation of Single-Strand Break Repair and Related Responses and their Role in Neuroprotection

单链断裂修复和相关反应的分子表征及其在神经保护中的作用

• 批准号: G0600776/1
• 负责人: Keith Caldecott
• 金额: $ 216.58万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0600776%2F1
• 关键词: Molecular; Characterisation; Single; Strand; Break

DNA breakage can lead to gene damage, cancer, and cell death, if not repaired rapidly and accurately. The commonest type of damage arising in cells is the single-strand break; a breakage of one of the two strands that comprise the DNA double helix. Recently, we have identified a direct link between an individual?s ability to repair single-strand breaks and hereditary neurodegenerative disease. These diseases are termed spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and ataxia oculomotor apraxia-1 (AOA1) and harbour mutations in the DNA repair genes Tdp1 and APTX, respectively. SCAN1 and AOA1 are associated with the progressive degeneration of specific parts of the brain (particularly the cerebellum), resulting ultimately in an inability of affected individuals to walk properly or to control normal movement. In this programme of work we will advance and extend our understanding of the single-strand break repair process, and address directly the relationship between this process and neurological function. This work will shed light on the link between DNA damage and neurodegeneration, and will hopefully provoke novel approaches for the treatment of certain types of neurological disease.

如果不能迅速准确地修复，DNA断裂会导致基因损伤、癌症和细胞死亡。细胞中最常见的损伤类型是单链断裂;构成DNA双螺旋的两条链中的一条断裂。最近，我们发现了一个人和另一个人之间的直接联系？修复单链断裂和遗传性神经退行性疾病的能力。这些疾病被称为脊髓小脑性共济失调伴轴突神经病变-1（SCAN 1）和共济失调眼用不能-1（AOA 1），并分别在DNA修复基因Tdp 1和APTX中发生突变。SCAN 1和AOA 1与大脑特定部位（特别是小脑）的进行性退化有关，最终导致受影响的个体无法正常行走或控制正常运动。在这项工作计划中，我们将推进和扩展我们对单链断裂修复过程的理解，并直接解决这个过程与神经功能之间的关系。这项工作将揭示DNA损伤和神经退行性变之间的联系，并有望为治疗某些类型的神经系统疾病提供新的方法。