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Current Pharmaceutical Biotechnology

Volume 11 Issue 5
ISSN: 1389-2010
eISSN: 1873-4316

 

   All Titles

  Defining Features and Exploring Chemical Modifications to Manipulate RNAa Activity
  pp.518-526 (9) Authors: Robert F. Place, Emily J. Noonan, Zeno Foldes-Papp, Long-Cheng Li
 
 
      Abstract

RNA interference (RNAi) is an evolutionary conserved mechanism by which small double-stranded RNA (dsRNA) — termed small interfering RNA (siRNA) — inhibit translation or degrade complementary mRNA sequences. Identifying features and enzymatic components of the RNAi pathway have led to the design of highly-effective siRNA molecules for laboratory and therapeutic application. RNA activation (RNAa) is a newly discovered mechanism of gene induction also triggered by dsRNAs termed small activating RNA (saRNA). It offers similar benefits as RNA interference (RNAi), while representing a new method of gene overexpression. In the present study, we identify features of RNAa and explore chemical modifications to saRNAs that improve the applicability of RNAa. We evaluate the rate of RNAa activity in order to define an optimal window of gene induction, while comparing the kinetic differences between RNAa and RNAi. We identify Ago2 as a conserved enzymatic component of both RNAa and RNAi implicating that saRNA may tolerate modification based on Ago2 function. As such, we define chemical modifications to saRNAs that manipulate RNAa activity, as well as exploit their effects to design saRNAs with enhanced medicinal properties. These findings reveal functional features of RNAa that may be utilized to augment saRNA function for mechanistic studies or the development of RNAa-based drugs.

 
  Keywords: Argonaute 2 (Ago2), cancer therapeutics, E-cadherin, gene promoter, p21, RNA activation (RNAa), RNA interference (RNAi), small activating RNA (saRNA), small interfering RNA (siRNA), strand modifications
  Affiliation: University of California San Francisco, Helen Diller Family Cancer Research Building, Department of Urology, MC 3110, 1450 3rd Street, PO Box 589001, San Francisco, CA 94158-9001, USA.
 
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