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Nucleic Acid Ther. 2019 Aug 20. doi: 10.1089/nat.2019.0806. [Epub ahead of print]

Phosphorothioate Antisense Oligonucleotides Bind P-Body Proteins and Mediate P-Body Assembly.

Author information

1
Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, California.

Abstract

Antisense oligonucleotides (ASOs) regulate gene expression by binding to complementary target RNA, and ASOs can be designed to take advantage of a growing array of post RNA binding molecular mechanisms. Intracellular trafficking of ASOs influences their efficacy. We have identified a number of membrane-less structures in the nucleus, nucleolus, and cytoplasm where phosphorothioate-modified ASOs (PS-ASOs) accumulate and have shown that PS-ASOs can induce the formation of new nuclear structures such as PS-bodies and paraspeckle-like structures. In this study, we report that PS-ASOs can localize to cytoplasmic processing bodies (P-bodies) and increase the number of P-bodies in cells. The antisense activity of PS-ASOs was not affected by the absence of essential P-body assembly proteins DDX6 and LSm14A. Moreover, the effects of PS-ASOs on P-body assembly were independent of their antisense activities. The phosphorothioate modification stabilizes the association between ASOs and cellular proteins and is essential for the P-body localization of ASOs. Since PS-ASOs bind to major P-body components, PS-ASOs may serve as scaffolds for P-body formation. Taken together, these results indicate that interactions of PS-ASO with proteins, rather than antisense activities, are essential for the dynamic interplay between PS-ASOs and P-bodies.

KEYWORDS:

P-body; antisense oligonucleotide; localization; phosphorothioate; protein

PMID:
31429620
DOI:
10.1089/nat.2019.0806

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