Single-molecule modeling of mRNA degradation by miRNA: Lessons from data.

Angelo Valleriani,Celine Sin,Davide Chiarugi

doi:10.1186/1752-0509-9-s3-s2

Abstract

Recent experimental results on the effect of miRNA on the decay of its target mRNA have been analyzed against a previously hypothesized single molecule degradation pathway. According to that hypothesis, the silencing complex (miRISC) first interacts with its target mRNA and then recruits the protein complexes associated with NOT1 and PAN3 to trigger deadenylation (and subsequent degradation) of the target mRNA. Our analysis of the experimental decay patterns allowed us to refine the structure of the degradation pathways at the single molecule level. Surprisingly, we found that if the previously hypothesized network was correct, only about 7% of the target mRNA would be regulated by the miRNA mechanism, which is inconsistent with the available knowledge. Based on systematic data analysis, we propose the alternative hypothesis that NOT1 interacts with miRISC before binding to the target mRNA. Moreover, we show that when miRISC binds alone to the target mRNA, the mRNA is degraded more slowly, probably through a deadenylation-independent pathway. The new biochemical pathway proposed here both fits the data and paves the way for new experimental work to identify new interactions.

Highlights

In living cells, the level of protein expression is thoroughly regulated
A possible interpretation is that the additional transition includes unknown biochemical degradation pathways which are independent of deadenylation. Supporting this hypothesis are the findings reported in [23]: they report that the binding of the miRISC complex to the target messenger RNAs (mRNAs) can promote the dissociation of PolyA-Binding Proteins (PABPs)
Summary and discussion In this paper, we show that the current hypothesis about the sequence of interactions between miRISC, its target mRNA and the factor NOT1 is not supported by the data

Summary

Introduction

Many crucial processes for this regulation occur at the post-transcriptional level. In this context, control mechanisms acting on messenger RNAs (mRNAs) play a pivotal role. The global picture emerging from the growing body of experimental evidence depicts a complex interaction network which affects the mRNAs available for translation. This network is composed of several biochemical pathways, often interwoven and cross-talking [7,8], involving mRNA binding proteins as well as non coding RNAs [9,10,11]. While there are a number of mechanisms responsible for mRNA degradation in eukaryotic cells [9], the decay of messages mediated by micro-RNAs (miRNAs) plays a prominent role in the control of gene expression [3,12,13]

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Conclusion