C9orf72 functions in the nucleus to regulate DNA damage repair
C9orf72 functions in the nucleus to regulate DNA damage repair
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C9orf72 在细胞核中发挥作用，调节 DNA 损伤修复
DOI：
10.1038/s41418-022-01074-0
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发表时间：
2022-10-11
影响因子：
12.4
通讯作者：
Li, Lei
中科院分区：
文献类型：
--
作者：
He, Liying;Liang, Jiaqi;Li, Lei
C9orf72基因内含子区域的六核苷酸GGGGCC重复扩增是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的病因。由重复扩增产生的毒性RNA和二肽重复序列（DPRs），包括多聚甘氨酸 - 精氨酸（poly - GR），在神经退行性变中已被广泛研究。此外，单倍体不足已被认为是一种疾病机制，但C9orf72缺失如何导致神经退行性变仍不清楚。在此，我们表明C9orf72缺失通过减弱非同源末端连接（NHEJ）修复加剧了多聚甘氨酸 - 精氨酸诱导的神经退行性变。我们证明C9orf72定位于细胞核，并迅速被招募到DNA损伤位点。C9orf72缺失通过减弱DNA - PK复合物组装和DNA损伤反应（DDR）信号传导导致NHEJ修复受损。在小鼠模型中，我们发现C9orf72缺失加剧了多聚甘氨酸 - 精氨酸诱导的神经元丢失、神经胶质细胞激活和神经肌肉功能缺陷。此外，在表达多聚甘氨酸 - 精氨酸的C9orf72缺失神经元中DNA损伤积累，导致PARP - 1过度激活。PARP - 1抑制剂挽救了用多聚甘氨酸 - 精氨酸肽处理的培养神经元的死亡。总之，我们的结果支持一种病理机制，即C9orf72单倍体不足与多聚甘氨酸 - 精氨酸诱导的DNA双链断裂协同作用，加剧了C9orf72 ALS/FTD患者中DNA损伤的积累和PARP - 1的过度激活。
The hexanucleotide GGGGCC repeat expansion in the intronic region of C9orf72 is the most common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeat expansion-generated toxic RNAs and dipeptide repeats (DPRs) including poly-GR, have been extensively studied in neurodegeneration. Moreover, haploinsufficiency has been implicated as a disease mechanism but how C9orf72 deficiency contributes to neurodegeneration remains unclear. Here, we show that C9orf72 deficiency exacerbates poly-GR-induced neurodegeneration by attenuating non-homologous end joining (NHEJ) repair. We demonstrate that C9orf72 localizes to the nucleus and is rapidly recruited to sites of DNA damage. C9orf72 deficiency resulted in impaired NHEJ repair through attenuated DNA-PK complex assembly and DNA damage response (DDR) signaling. In mouse models, we found that C9orf72 deficiency exacerbated poly-GR-induced neuronal loss, glial activation, and neuromuscular deficits. Furthermore, DNA damage accumulated in C9orf72-deficient neurons that expressed poly-GR, resulting in excessive activation of PARP-1. PARP-1 inhibition rescued neuronal death in cultured neurons treated with poly-GR peptides. Together, our results support a pathological mechanism where C9orf72 haploinsufficiency synergizes with poly-GR-induced DNA double-strand breaks to exacerbate the accumulation of DNA damage and PARP-1 overactivation in C9orf72 ALS/FTD patients.