C9orf72 functions in the nucleus to regulate DNA damage repair

doi:10.1038/s41418-022-01074-0

	C9orf72 functions in the nucleus to regulate DNA damage repair
	He, Liying1,2 ; Liang, Jiaqi1,2 ; Chen, Chaonan1 ; Chen, Jijun 3; Shen, Yihui1,2 ; Sun, Shuangshuang1,2 ; Li, Lei1
	2022-10
发表期刊	CELL DEATH & DIFFERENTIATION
ISSN	1350-9047
EISSN	1476-5403
发表状态	已发表
DOI	10.1038/s41418-022-01074-0
摘要	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.
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收录类别	SCI ; SCIE ; SCOPUS
语种	英语
资助项目	National Natural Science Foundation of China["91949117","31871044"]
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Cell Biology
WOS记录号	WOS:000865912600002
出版者	SPRINGERNATURE
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/235970
专题	生命科学与技术学院_博士生生命科学与技术学院_PI研究组_李磊组生命科学与技术学院_硕士生
通讯作者	Li, Lei
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Inst Brain Intelligence Technol, Zhangjiang Lab, Shanghai, Peoples R China
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
第一作者的第一单位	生命科学与技术学院
推荐引用方式 GB/T 7714	He, Liying,Liang, Jiaqi,Chen, Chaonan,et al. C9orf72 functions in the nucleus to regulate DNA damage repair[J]. CELL DEATH & DIFFERENTIATION,2022.
APA	He, Liying.,Liang, Jiaqi.,Chen, Chaonan.,Chen, Jijun.,Shen, Yihui.,...&Li, Lei.(2022).C9orf72 functions in the nucleus to regulate DNA damage repair.CELL DEATH & DIFFERENTIATION.
MLA	He, Liying,et al."C9orf72 functions in the nucleus to regulate DNA damage repair".CELL DEATH & DIFFERENTIATION (2022).