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Quantifying the effect of ribosomal density on mRNA stability.

ABSTRACT: Gene expression is a fundamental cellular process by which proteins are eventually synthesized based on the information coded in the genes. This process includes four major steps: transcription of the DNA segment corresponding to a gene to mRNA molecules, the degradation of the mRNA molecules, the translation of mRNA molecules to proteins by the ribosome and the degradation of the proteins. We present an innovative quantitative study of the interaction between the gene translation stage and the mRNA degradation stage using large scale genomic data of S. cerevisiae, which include measurements of mRNA levels, mRNA half-lives, ribosomal densities and protein abundances, for thousands of genes. The reported results support the conjecture that transcripts with higher ribosomal density, which is related to the translation stage, tend to have elevated half-lives, and we suggest a novel quantitative estimation of the strength of this relation. Specifically, we show that on average, an increase of 78% in ribosomal density yields an increase of 25% in mRNA half-life, and that this relation between ribosomal density and mRNA half-life is not function specific. In addition, our analyses demonstrate that ribosomal density along the entire ORF, and not in specific locations, has a significant effect on the transcript half-life. Finally, we show that the reported relation cannot be explained by different expression levels among genes. A plausible explanation for the reported results is that ribosomes tend to protect the mRNA molecules from the exosome complexes degrading them; however, additional non-mutually exclusive possible explanations for the reported relation and experiments for their verifications are discussed in the paper.

SUBMITTER: Edri S

PROVIDER: S-EPMC4096589 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Quantifying the effect of ribosomal density on mRNA stability.

Edri Shlomit S Tuller Tamir T

PloS one 20140714 7

Gene expression is a fundamental cellular process by which proteins are eventually synthesized based on the information coded in the genes. This process includes four major steps: transcription of the DNA segment corresponding to a gene to mRNA molecules, the degradation of the mRNA molecules, the translation of mRNA molecules to proteins by the ribosome and the degradation of the proteins. We present an innovative quantitative study of the interaction between the gene translation stage and the ...[more]

PMID: 25020060

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Project description:OBJECTIVES:To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment. DESIGN:Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke. MAIN OUTCOME MEASURES:Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol. RESULTS:Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population. CONCLUSIONS:Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.

Dataset Information

Quantifying the effect of ribosomal density on mRNA stability.

Publications

Quantifying the effect of ribosomal density on mRNA stability.

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