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DOI	10.1073/PNAS.2022940118
	Cag rnas induce dna damage and apoptosis by silencing nudt16 expression in polyglutamine degeneration
	Peng S.; Guo P.; Lin X.; An Y.; Sze K.H.; Lau M.H.Y.; Chen Z.S.; Wang Q.; Li W.; Sun J.K.-L.; Ma S.Y.; Chan T.-F.; Lau K.-F.; Ngo J.C.K.; Kwan K.M.; Wong C.-H.; Lam S.L.; Zimmerman S.C.; Tuccinardi T.; Zuo Z.; Au-Yeung H.Y.; Chow H.-M.; Chan H.Y.E.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:19
英文摘要	DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNAexpressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases. © 2021 National Academy of Sciences. All rights reserved.
语种	英语
scopus关键词	agents affecting nucleic acid metabolism; ATM protein; ATR protein; caspase 3; checkpoint kinase 1; checkpoint kinase 2; DB213; heteroduplex; nucleoside diphosphatase; nucleoside diphosphate linked moiety X type motif 16 protein; polyglutamine; protein homer 1; protein p53; RNA; RNA induced silencing complex; small CAG RNA; synapsin I; unclassified drug; benzamidine derivative; DB213 compound; huntingtin; inorganic pyrophosphatase; messenger RNA; Nudt16 protein, human; peptide; polyglutamine; RNA; adult; animal experiment; animal model; animal tissue; apoptosis; Article; binding affinity; binding assay; CAG repeat; comet assay; confocal microscopy; controlled study; dissociation constant; DNA damage; down regulation; Drosophila; embryo; gene; gene expression level; gene overexpression; gene silencing; heteronuclear multiple bond correlation; human; human cell; Huntington chorea; immunocytochemistry; in situ hybridization; isothermal titration calorimetry; mouse; nerve degeneration; nonhuman; nuclear Overhauser effect; nucleoside diphosphate linked moiety X type motif 16 gene; open field test; proteinosis; rat; real time reverse transcription polymerase chain reaction; RNA sequence; RNA sequencing; rotarod test; Western blotting; animal; apoptosis; C57BL mouse; disease model; drug effect; gene expression regulation; genetics; Huntington chorea; metabolism; molecular dynamics; RNA interference; transgenic mouse; trinucleotide repeat; tumor cell line; Animals; Apoptosis; Benzamidines; Cell Line, Tumor; Disease Models, Animal; DNA Damage; Gene Expression Regulation; Humans; Huntingtin Protein; Huntington Disease; Mice, Inbred C57BL; Mice, Transgenic; Molecular Dynamics Simulation; Peptides; Pyrophosphatases; RNA; RNA Interference; RNA, Messenger; Trinucleotide Repeat Expansion
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251189
作者单位	Laboratory of Drosophila Research, Chinese University of Hong Kong, Hong Kong; School of Life Sciences, Chinese University of Hong Kong, Hong Kong; Department of Chemistry, Chinese University of Hong Kong, Hong Kong; School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510006, China; Department of Microbiology, University of Hong Kong, Hong Kong; Department of Chemistry, State Key Laboratory of Synthetic Chemistry, University of Hong Kong, Hong Kong; School of Pharmacy, Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Agrobiotechnology, Chinese University of Hong Kong, Hong Kong; Gerald Choa Neuroscience Centre, Chinese University of Hong Kong, Hong Kong; School of Life Sciences, Chinese University of Hong Kong, Nexus of Rare Neurodegenerative Diseases, Hong Kong; Centre for Cell and Developmental Biology, Chinese University of Hong Kong, Hong Kong; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United St...
推荐引用方式 GB/T 7714	Peng S.,Guo P.,Lin X.,et al. Cag rnas induce dna damage and apoptosis by silencing nudt16 expression in polyglutamine degeneration[J],2021,118(19).
APA	Peng S..,Guo P..,Lin X..,An Y..,Sze K.H..,...&Chan H.Y.E..(2021).Cag rnas induce dna damage and apoptosis by silencing nudt16 expression in polyglutamine degeneration.Proceedings of the National Academy of Sciences of the United States of America,118(19).
MLA	Peng S.,et al."Cag rnas induce dna damage and apoptosis by silencing nudt16 expression in polyglutamine degeneration".Proceedings of the National Academy of Sciences of the United States of America 118.19(2021).