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Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs
Huang, Huang1; Qiao, Renping2; Zhao, Deyao3; Zhang, Tong2; Li, Youxian1; Yi, Fan1; Lai, Fangfang1; Hong, Junmei1; Ding, Xianfeng3; Yang, Zhenjun2; Zhang, Lihe2; Du, Quan1; Liang, Zicai1
刊名NUCLEIC ACIDS RESEARCH
2009-12-01
DOI10.1093/nar/gkp835
37期:22页:7560-7569
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]ARGONAUTE SILENCING COMPLEX ; OFF-TARGET ACTIVITY ; MAMMALIAN-CELLS ; INTERFERENCE ; DISEASE ; THERAPEUTICS ; TRANSLATION ; REVEALS ; MIRNAS ; GENE
英文摘要

Silencing specificity is a critical issue in the therapeutic applications of siRNA, particularly in the treatment of single nucleotide polymorphism (SNP) diseases where discrimination against single nucleotide variation is demanded. However, no generally applicable guidelines are available for the design of such allele-specific siRNAs. In this paper, the issue was approached by using a reporter-based assay. With a panel of 20 siRNAs and 240 variously mismatched target reporters, we first demonstrated that the mismatches were discriminated in a position-dependent order, which was however independent of their sequence contexts using position 4th, 12th and 17th as examples. A general model was further built for mismatch discrimination at all positions using 230 additional reporter constructs specifically designed to contain mismatches distributed evenly along the target regions of different siRNAs. This model was successfully employed to design allele-specific siRNAs targeting disease-causing mutations of PIK3CA gene at two SNP sites. Furthermore, conformational distortion of siRNA-target duplex was observed to correlate with the compromise of gene silencing. In summary, these findings could dramatically simplify the design of allele-specific siRNAs and might also provide guide to increase the specificity of therapeutic siRNAs.

语种英语
WOS记录号WOS:000272935000027
项目编号30873187 ; 30771085 ; 30871385 ; 5092011 ; 2006AA02Z104 ; 2007AA02Z165 ; 2007CB512100 ; 20070001011 ; 200800010019
资助机构National Natural Science Foundation of China ; Beijing Natural Science Foundation ; National High-tech R&amp ; D Program of China ; National Basic Research Program of China ; National 985 Program ; Department of Education of China
引用统计
被引频次:31[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/60862
专题北京大学第一临床医学院_门诊部
北京大学药学院
北京大学药学院_药物化学系
作者单位1.Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China
2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100083, Peoples R China
3.Zhejiang Sci Tech Univ, Sch Life Sci, Hangzhou 310018, Peoples R China
推荐引用方式
GB/T 7714
Huang, Huang,Qiao, Renping,Zhao, Deyao,et al. Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs[J]. NUCLEIC ACIDS RESEARCH,2009,37(22):7560-7569.
APA Huang, Huang.,Qiao, Renping.,Zhao, Deyao.,Zhang, Tong.,Li, Youxian.,...&Liang, Zicai.(2009).Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs.NUCLEIC ACIDS RESEARCH,37(22),7560-7569.
MLA Huang, Huang,et al."Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs".NUCLEIC ACIDS RESEARCH 37.22(2009):7560-7569.
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