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MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms
Yan Zeng1, Rui Yi, Bryan R Cullen
1Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
MicroRNAs (miRNAs) are endogenously encoded small noncoding RNAs, derived by processing of short RNA hairpins, that can inhibit the translation of mRNAs bearing partially complementary target sequences. In contrast, small interfering RNAs (siRNAs), which are derived by processing of long double-stranded RNAs and are often of exogenous origin, degrade mRNAs bearing fully complementary sequences. Here, we demonstrate that an endogenously encoded human miRNA is able to cleave an mRNA bearing fully complementary target sites, whereas an exogenously supplied siRNA can inhibit the expression of an mRNA bearing partially complementary sequences without inducing detectable RNA cleavage. These data suggest that miRNAs and siRNAs can use similar mechanisms to repress mRNA expression and that the choice of mechanism may be largely or entirely determined by the degree of complementary of the RNA target.
Insights
Endogenous microRNAs (miRNAs) can cleave mRNA targets, while exogenous small interfering RNAs (siRNAs) can inhibit translation. These findings suggest RNA complementarity dictates the mechanism of gene silencing by both miRNAs and siRNAs.
Area of Science:
- Molecular Biology
- Genetics
- RNA Biology
Background:
- MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit mRNA translation.
- Small interfering RNAs (siRNAs) are often exogenous and degrade mRNAs.
- Both miRNA and siRNA pathways are crucial for gene regulation.
Purpose of the Study:
- To investigate the mechanisms of gene silencing by endogenous miRNAs and exogenous siRNAs.
- To determine if miRNAs can cleave mRNA targets and if siRNAs can inhibit translation without cleavage.
- To explore the role of target complementarity in miRNA and siRNA function.
Main Methods:
- Utilized endogenous human miRNA and exogenous siRNA in experimental systems.
- Assessed mRNA cleavage and translational inhibition.
- Analyzed the complementarity between RNA molecules and their targets.
Main Results:
- Demonstrated that an endogenous human miRNA can cleave an mRNA with fully complementary target sites.
- Showed that an exogenously supplied siRNA can inhibit mRNA expression with partially complementary sequences without inducing cleavage.
- Highlighted distinct but potentially overlapping mechanisms for miRNA and siRNA action.
Conclusions:
- miRNAs and siRNAs may employ similar pathways for mRNA repression.
- The degree of complementarity between the small RNA and its target likely dictates the mechanism of action (cleavage vs. translational inhibition).
- This study provides new insights into the functional divergence and convergence of small RNA pathways in gene regulation.