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D-Isonucleotide (isoNA) incorporation around cleavage site of passenger strand promotes the vibration of Ago2-PAZ domain and enhances in vitro potency of siRNA
Huang, Ye1,5,6; Tian, Miao1; Zhang, Yichao2; Sheng, Gang3; Chen, Zhuo1; Ma, Yuan1; Chen, Yue1; Peng, Yihong4; Zhao, Yi-Lei2; Wang, Yanli3; Zhang, Lihe1; Yang, Zhenjun1
刊名ORGANIC & BIOMOLECULAR CHEMISTRY
2015
DOI10.1039/c5ob01119a
13期:44页:10825-10833
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Organic
研究领域[WOS]Chemistry
关键词[WOS]Silencing Activity ; Rna Interference ; Risc ; Stability ; Expression ; Complexes ; Protein ; Cells
英文摘要

It has been demonstrated that passenger strand cleavage is important for the activation of RNA-induced silencing complex (RISC), which is a crucial step for siRNA-mediated gene silencing. Herein, we report that isonucleotide (isoNA) modification around the cleavage site of the passenger strand would affect the in vitro potency of modified siRNAs by altering the motion pattern of the Ago2-PAZ domain. According to western blotting, q-PCR and antiviral test results, we proved that D-isonucleotide (isoNA) modification at the position 8 of the passenger strand (siMek1-S08D), which is adjacent to the cleavage site, markedly improved the in vitro potency of the modified siRNA, whereas siRNAs with D-isoNA incorporation at position 9 (siMek1-S09D) or L-isoNA incorporation at positions 8 and 9 (siMek1-S08L, siMek1-S09L) displayed lower activity compared to native siRNA. Kinetics evaluation of passenger strand cleavage induced by T. thermophilus Ago (Tt-Ago) showed that D-isoNA modification at position 8 of the passenger strand had no significant influence on the cleavage rate, but L-isoNA modification at position 8 slowed the cleavage rate markedly. Moreover, the results of molecular dynamics simulations showed that D-isoNA modification at position 8 affected the open-close motion of the PAZ domain in the Ago/siRNA complex, which may promote the loading of RISC and release of a passenger strand cleavage product, and consequently accelerate the activation of RISC and enhance silencing activity. However, D-isoNA modification at position 9 or L-isoNA modification at position 8 or 9 exerted opposite influences on the motion of the Ago-PAZ domain.

语种英语
WOS记录号WOS:000364077400006
通讯作者邮箱yileizhao@sjtu.edu.cn
项目编号2012AA022501 ; 2012CB720604 ; 2013CB966800 ; 2013CB966802 ; 20932001 ; 21377085
资助机构Ministry of Science and Technology of China ; National Natural Science Foundation of China
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/62414
专题北京大学药学院
北京大学医学部管理机构_后勤处
北京大学基础医学院
北京大学药学院_药物化学系
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, State Key Lab Microbial Metab, Shanghai 200030, Peoples R China
3.Chinese Acad Sci, Inst Biophys, Lab Noncoding RNA, Beijing 100080, Peoples R China
4.Peking Univ, Sch Basic Med Sci, Dept Microbiol, Beijing 100871, Peoples R China
5.Peking Union Med Coll, Inst Mat Med, Dept New Drug Res & Dev, Beijing 100021, Peoples R China
6.Chinese Acad Med Sci, Beijing 100730, Peoples R China
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GB/T 7714
Huang, Ye,Tian, Miao,Zhang, Yichao,et al. D-Isonucleotide (isoNA) incorporation around cleavage site of passenger strand promotes the vibration of Ago2-PAZ domain and enhances in vitro potency of siRNA[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2015,13(44):10825-10833.
APA Huang, Ye.,Tian, Miao.,Zhang, Yichao.,Sheng, Gang.,Chen, Zhuo.,...&Yang, Zhenjun.(2015).D-Isonucleotide (isoNA) incorporation around cleavage site of passenger strand promotes the vibration of Ago2-PAZ domain and enhances in vitro potency of siRNA.ORGANIC & BIOMOLECULAR CHEMISTRY,13(44),10825-10833.
MLA Huang, Ye,et al."D-Isonucleotide (isoNA) incorporation around cleavage site of passenger strand promotes the vibration of Ago2-PAZ domain and enhances in vitro potency of siRNA".ORGANIC & BIOMOLECULAR CHEMISTRY 13.44(2015):10825-10833.
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