7D12

NMR solution structures of CAG RNA-DB213 binding complex

7D12 の概要

• エントリーDOI: 10.2210/pdb7d12/pdb
• 分子名称: RNA (5'-R(*GP*CP*AP*GP*CP*AP*GP*CP*UP*UP*CP*GP*GP*CP*AP*GP*CP*AP*GP*C)-3'), N'-{(Z)-amino[4-(amino{[3-(dimethylammonio)propyl]iminio}methyl)phenyl]methylidene}-N,N-dimethylpropane-1,3-diaminium, SODIUM ION (3 entities in total)
• 機能のキーワード: rna, cag rna, ligand, complex
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7118.28

構造登録者

Chan, H.Y.E.,Guo, P. (登録日: 2020-09-12, 公開日: 2021-05-12, 最終更新日: 2024-05-01)

主引用文献

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.,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.
CAG RNAs induce DNA damage and apoptosis by silencing NUDT16 expression in polyglutamine degeneration.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: 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 () 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 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing 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 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.

PubMed: 33947817
DOI: 10.1073/pnas.2022940118

実験手法

SOLUTION NMR