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Complex degradation processes lead to non-exponential decay patterns and age-dependent decay rates of messenger RNA.

Deneke C, Lipowsky R, Valleriani A - PLoS ONE (2013)

Bottom Line: Furthermore, a variety of different and complex biochemical pathways for mRNA degradation have been identified.Next, we develop a theory, formulated as a Markov chain model, that recapitulates some aspects of the multi-step nature of mRNA degradation.We apply our theory to experimental data for yeast and explicitly derive the lifetime distribution of the corresponding mRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.

ABSTRACT
Experimental studies on mRNA stability have established several, qualitatively distinct decay patterns for the amount of mRNA within the living cell. Furthermore, a variety of different and complex biochemical pathways for mRNA degradation have been identified. The central aim of this paper is to bring together both the experimental evidence about the decay patterns and the biochemical knowledge about the multi-step nature of mRNA degradation in a coherent mathematical theory. We first introduce a mathematical relationship between the mRNA decay pattern and the lifetime distribution of individual mRNA molecules. This relationship reveals that the mRNA decay patterns at steady state expression level must obey a general convexity condition, which applies to any degradation mechanism. Next, we develop a theory, formulated as a Markov chain model, that recapitulates some aspects of the multi-step nature of mRNA degradation. We apply our theory to experimental data for yeast and explicitly derive the lifetime distribution of the corresponding mRNAs. Thereby, we show how to extract single-molecule properties of an mRNA, such as the age-dependent decay rate and the residual lifetime. Finally, we analyze the decay patterns of the whole translatome of yeast cells and show that yeast mRNAs can be grouped into three broad classes that exhibit three distinct decay patterns. This paper provides both a method to accurately analyze non-exponential mRNA decay patterns and a tool to validate different models of degradation using decay data.

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Related in: MedlinePlus

Prototypical pathways of mRNA degradation.In panel A degradation is depicted as a relatively simple process determined by only a single step, e.g. by unspecific and fast endonucleolytic decay, such as the degradation pathway mediated by RNase E in prokaryotic cells. In panel B, instead, we show a schematic representation of the degradation pathway known as decapping which is one of the main degradation mechanisms in eukaryotic cells. The decapping mechanism consists of several biochemical steps, possibly triggered by a specific miRNA, which contribute to destabilize the mRNA until complete degradation takes place. This mechanism can be considered as a prototype of multi-step degradation.
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pone-0055442-g002: Prototypical pathways of mRNA degradation.In panel A degradation is depicted as a relatively simple process determined by only a single step, e.g. by unspecific and fast endonucleolytic decay, such as the degradation pathway mediated by RNase E in prokaryotic cells. In panel B, instead, we show a schematic representation of the degradation pathway known as decapping which is one of the main degradation mechanisms in eukaryotic cells. The decapping mechanism consists of several biochemical steps, possibly triggered by a specific miRNA, which contribute to destabilize the mRNA until complete degradation takes place. This mechanism can be considered as a prototype of multi-step degradation.

Mentions: First, it is important to distinguish between single-step and multi-step degradation. On the one hand, endonucleolytic degradation, depicted in Fig. 2A, is a prototype of single-step degradation. On the other hand, the decapping mechanism shown in Fig. 2B is a prototype of multi-step degradation. The lifetime distribution of the mRNAs will resemble an exponential function if there is only one rate limiting process relevant for degradation as in Fig. 2A. Conversely, the lifetime distribution will have a more complicated form if several biochemical modifications are necessary as in Fig. 2B, and it will be directly related to the details of the particular degradation pathway. Relatively simple processes like those illustrated in Figs. 2A and 2B can be described within the framework of continuous-time Markov chains, which is a common mathematical tool in stochastic modeling of biological processes (see Models and Methods for details). More complex degradation processes may instead require different models. Nevertheless, there exists a general mathematical framework that links the degradation process to the decay pattern.


Complex degradation processes lead to non-exponential decay patterns and age-dependent decay rates of messenger RNA.

Deneke C, Lipowsky R, Valleriani A - PLoS ONE (2013)

Prototypical pathways of mRNA degradation.In panel A degradation is depicted as a relatively simple process determined by only a single step, e.g. by unspecific and fast endonucleolytic decay, such as the degradation pathway mediated by RNase E in prokaryotic cells. In panel B, instead, we show a schematic representation of the degradation pathway known as decapping which is one of the main degradation mechanisms in eukaryotic cells. The decapping mechanism consists of several biochemical steps, possibly triggered by a specific miRNA, which contribute to destabilize the mRNA until complete degradation takes place. This mechanism can be considered as a prototype of multi-step degradation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569439&req=5

pone-0055442-g002: Prototypical pathways of mRNA degradation.In panel A degradation is depicted as a relatively simple process determined by only a single step, e.g. by unspecific and fast endonucleolytic decay, such as the degradation pathway mediated by RNase E in prokaryotic cells. In panel B, instead, we show a schematic representation of the degradation pathway known as decapping which is one of the main degradation mechanisms in eukaryotic cells. The decapping mechanism consists of several biochemical steps, possibly triggered by a specific miRNA, which contribute to destabilize the mRNA until complete degradation takes place. This mechanism can be considered as a prototype of multi-step degradation.
Mentions: First, it is important to distinguish between single-step and multi-step degradation. On the one hand, endonucleolytic degradation, depicted in Fig. 2A, is a prototype of single-step degradation. On the other hand, the decapping mechanism shown in Fig. 2B is a prototype of multi-step degradation. The lifetime distribution of the mRNAs will resemble an exponential function if there is only one rate limiting process relevant for degradation as in Fig. 2A. Conversely, the lifetime distribution will have a more complicated form if several biochemical modifications are necessary as in Fig. 2B, and it will be directly related to the details of the particular degradation pathway. Relatively simple processes like those illustrated in Figs. 2A and 2B can be described within the framework of continuous-time Markov chains, which is a common mathematical tool in stochastic modeling of biological processes (see Models and Methods for details). More complex degradation processes may instead require different models. Nevertheless, there exists a general mathematical framework that links the degradation process to the decay pattern.

Bottom Line: Furthermore, a variety of different and complex biochemical pathways for mRNA degradation have been identified.Next, we develop a theory, formulated as a Markov chain model, that recapitulates some aspects of the multi-step nature of mRNA degradation.We apply our theory to experimental data for yeast and explicitly derive the lifetime distribution of the corresponding mRNAs.

View Article: PubMed Central - PubMed

Affiliation: Department of Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.

ABSTRACT
Experimental studies on mRNA stability have established several, qualitatively distinct decay patterns for the amount of mRNA within the living cell. Furthermore, a variety of different and complex biochemical pathways for mRNA degradation have been identified. The central aim of this paper is to bring together both the experimental evidence about the decay patterns and the biochemical knowledge about the multi-step nature of mRNA degradation in a coherent mathematical theory. We first introduce a mathematical relationship between the mRNA decay pattern and the lifetime distribution of individual mRNA molecules. This relationship reveals that the mRNA decay patterns at steady state expression level must obey a general convexity condition, which applies to any degradation mechanism. Next, we develop a theory, formulated as a Markov chain model, that recapitulates some aspects of the multi-step nature of mRNA degradation. We apply our theory to experimental data for yeast and explicitly derive the lifetime distribution of the corresponding mRNAs. Thereby, we show how to extract single-molecule properties of an mRNA, such as the age-dependent decay rate and the residual lifetime. Finally, we analyze the decay patterns of the whole translatome of yeast cells and show that yeast mRNAs can be grouped into three broad classes that exhibit three distinct decay patterns. This paper provides both a method to accurately analyze non-exponential mRNA decay patterns and a tool to validate different models of degradation using decay data.

Show MeSH
Related in: MedlinePlus