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RNA. 2006 Jul;12(7):1197-205. Epub 2006 May 8.

Position-specific chemical modification of siRNAs reduces "off-target" transcript silencing.

Author information

  • 1Rosetta Inpharmatics, LLC, Seattle, WA 98109, USA. aimee_jackson@merck.com

Abstract

Transfected siRNAs regulate numerous transcripts sharing limited complementarity to the RNA duplex. This unintended ("off-target") silencing can hinder the use of RNAi to define gene function. Here we describe position-specific, sequence-independent chemical modifications that reduced silencing of partially complementary transcripts by all siRNAs tested. Silencing of perfectly matched targets was unaffected by these modifications. The chemical modification also reduced off-target phenotypes in growth inhibition studies. Key to the modification was 2'-O-methyl ribosyl substitution at position 2 in the guide strand, which reduced silencing of most off-target transcripts with complementarity to the seed region of the siRNA guide strand. The sharp position dependence of 2'-O-methyl ribosyl modification contrasts with the broader position dependence of base-pair substitutions within the seed region, suggesting a role for position 2 of the guide strand distinct from its effects on pairing to target transcripts.

PMID:
16682562
[PubMed - indexed for MEDLINE]
PMCID:
PMC1484422
Free PMC Article

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