Hexanucleotide repeat expansions represent the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, though the mechanisms by which such expansions cause neurodegeneration are poorly understood. We report elevated levels of DNA–RNA hybrids (R-loops) and double strand breaks in rat neurons, human cells and C9orf72 ALS patient spinal cord tissues. Accumulation of endogenous DNA damage is concomitant with defective ATM-mediated DNA repair signaling and accumulation of protein-linked DNA breaks. We reveal that defective ATM-mediated DNA repair is a consequence of P62 accumulation, which impairs H2A ubiquitylation and perturbs ATM signaling. Virus-mediated expression of C9orf72-related RNA and dipeptide repeats in the mouse central nervous system increases double strand breaks and ATM defects and triggers neurodegeneration. These findings identify R-loops, double strand breaks and defective ATM-mediated repair as pathological consequences of C9orf72 expansions and suggest that C9orf72-linked neurodegeneration is driven at least partly by genomic instability.

中文翻译：

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C9orf72扩增破坏ATM介导的染色体断裂修复

六核苷酸重复扩增代表肌萎缩性侧索硬化症（ALS）和额颞叶痴呆的最常见遗传原因，尽管这种扩增引起神经退行性变的机制了解甚少。我们报道了在大鼠神经元，人类细胞和C9orf72 ALS患者的脊髓组织中DNA–RNA杂合体（R环）水平升高和双链断裂。内源性DNA损伤的积累伴随着有缺陷的ATM介导的DNA修复信号传导和蛋白质连接的DNA断裂的积累。我们揭示缺陷的ATM介导的DNA修复是P62积累的结果，P62积累会损害H2A泛素化并扰乱ATM信号传导。病毒介导的C9 orf表达小鼠中枢神经系统中的72个相关RNA和二肽重复序列增加了双链断裂和ATM缺陷并触发了神经变性。这些发现将R环，双链断裂和有缺陷的ATM介导的修复鉴定为C9orf72扩增的病理结果，并表明C9orf72连锁的神经变性至少部分地由基因组不稳定性驱动。