Functional siRNAs and miRNAs exhibit strand bias
Open accessAbstract
Both microRNAs (miRNA) and small interfering RNAs (siRNA) share a common set of cellular proteins (Dicer and the RNA-induced silencing complex [RISC]) to elicit RNA interference. In the following work, a statistical analysis of the internal stability of published miRNA sequences in the context of miRNA precursor hairpins revealed enhanced flexibility of miRNA precursors, especially at the 5'-anti-sense (AS) terminal base pair. The same trend was observed in siRNA, with functional duplexes displaying a lower internal stability (Delta0.5 kcal/mol) at the 5'-AS end than nonfunctional duplexes. Average internal stability of siRNA molecules retrieved from plant cells after introduction of long RNA sequences also shows this characteristic thermodynamic signature. Together, these results suggest that the thermodynamic properties of siRNA play a critical role in determining the molecule's function and longevity, possibly biasing the steps involved in duplex unwinding and strand retention by RISC.
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The strand in which the 5' end is less tightly paired to its complement remains associated with Ago and performs the functions of the mature miRNA.
“Studies investigating the relative thermodynamic stability of the two ends of the pre-miRNA duplex indicated that the strand in which the 5Ј end is less tightly paired to its complement remains associated with Ago and performs the functions of the mature miRNA (Khvorova et al., 2003;Schwarz et al., 2003).”
From Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes (2013) · cites this paper as Khvorova et al., 2003
The first four nucleotides of each end of the duplex are believed to establish thermodynamic asymmetry, and the difference of a single extra hydrogen bond is sufficient to drive preferential loading of the less stable strand in vitro.
“The first four nucleotides of each end of the duplex are believed to establish thermodynamic asymmetry, and the difference of a single extra hydrogen bond is sufficient to drive preferential loading of the less stable strand in vitro (Khvorova, Reynolds, & Jayasena, 2003; Krol et al., 2004; Schwarz et al., 2003).”
From microRNA strand selection: Unwinding the rules (2021) · cites this paper as Khvorova, Reynolds, & Jayasena, 2003
The selection of the 5p or 3p strand is based in part on the thermodynamic stability at the 5' ends of the miRNA duplex or a 5' U at nucleotide position 1.
“The selection of the 5p or 3p strand is based in part on the thermodynamic stability at the 5′ ends of the miRNA duplex or a 5′ U at nucleotide position 1 (34).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [34]
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- Authors
- Khvorova, A., Reynolds, A., & Jayasena, S. D.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Jayasena, Sumedha D.
- ORCID
- Khvorova, Anastasia
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 115
- Issue
- 2
- Pages
- 209-216
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2071596792
- Cited by
- 2,645
- References
- 29
- Citations by year
- 2026: 39 · 2025: 66 · 2024: 48 · 2023: 62 · 2022: 64 · 2021: 69 · 2020: 81 · 2019: 85 · 2018: 88 · 2017: 103 · 2016: 80 · 2015: 142 · 2014: 132 · 2013: 148 · 2012: 179
- FWCI
- 52.16
- Type
- journal article
- Language
- en
- Update notices
- erratum (2003-11-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- siRNA, microRNA, strand bias, RNA interference, RNA duplex stability, thermodynamic stability, RNA-induced silencing complex, Dicer
- MeSH terms
- Animals, Base Sequence, Cell Line, Drosophila, Humans, Models, Biological, Proteins, RNA Precursors, RNA, Messenger, Thermodynamics, Caenorhabditis elegans, RNA, Plant, Base Pairing, Base Pair Mismatch, Gene Silencing, RNA, Small Interfering, MicroRNAs, Mice
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