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

DNA断裂如果不能迅速和准确地修复，可能会导致基因损伤、癌症和细胞死亡。细胞中最常见的损伤类型是单链断裂，即组成DNA双螺旋的两条链中的一条断裂。最近，我们发现了个体--S修复单链断裂的能力与遗传性神经退行性疾病之间的直接联系。这些疾病被称为脊髓小脑性共济失调伴轴索神经病-1(SCAN1)和共济失调动眼运动性失用-1(AOA1)，DNA修复基因Tdp1和aptX分别存在突变。SCAN1和AOA1与大脑特定部分(特别是小脑)的进行性退化有关，最终导致受影响的人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，并直接讨论这一过程与神经功能之间的关系。这项工作将阐明DNA损伤和神经退行性变之间的联系，并有望引发治疗某些类型神经疾病的新方法。

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.