Abasic pivot substitution harnesses target specificity of RNA interference

Hye-Sook Lee, Heeyoung Seok, Dong Ha Lee, Juyoung Ham, Wooje Lee, Emilia Moonkyung Youm, Jin Seon Yoo, Yong-Seung Lee, Eun-Sook Jang () and Sung Wook Chi ()
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Hye-Sook Lee: College of Life Sciences and Biotechnology, Korea University
Heeyoung Seok: College of Life Sciences and Biotechnology, Korea University
Dong Ha Lee: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University
Juyoung Ham: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University
Wooje Lee: College of Life Sciences and Biotechnology, Korea University
Emilia Moonkyung Youm: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University
Jin Seon Yoo: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University
Yong-Seung Lee: EncodeGEN Co. Ltd.
Eun-Sook Jang: Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University
Sung Wook Chi: College of Life Sciences and Biotechnology, Korea University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Gene silencing via RNA interference inadvertently represses hundreds of off-target transcripts. Because small interfering RNAs (siRNAs) can function as microRNAs, avoiding miRNA-like off-target repression is a major challenge. Functional miRNA–target interactions are known to pre-require transitional nucleation, base pairs from position 2 to the pivot (position 6). Here, by substituting nucleotide in pivot with abasic spacers, which prevent base pairing and alleviate steric hindrance, we eliminate miRNA-like off-target repression while preserving on-target activity at ∼80–100%. Specifically, miR-124 containing dSpacer pivot substitution (6pi) loses seed-mediated transcriptome-wide target interactions, repression activity and biological function, whereas other conventional modifications are ineffective. Application of 6pi allows PCSK9 siRNA to efficiently lower plasma cholesterol concentration in vivo, and abolish potentially deleterious off-target phenotypes. The smallest spacer, C3, also shows the same improvement in target specificity. Abasic pivot substitution serves as a general means to harness the specificity of siRNA experiments and therapeutic applications.

Date: 2015
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DOI: 10.1038/ncomms10154

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