Novel mRNA-specific effects of ribosome drop-off on translation rate and polysome profile.
Novel mRNA-specific effects of ribosome drop-off on translation rate and polysome profile.
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DOI：
10.1371/journal.pcbi.1005555
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发表时间：
2017-05
影响因子：
4.3
通讯作者：
Romano MC
中科院分区：
文献类型：
--
作者：
Bonnin P;Kern N;Young NT;Stansfield I;Romano MC
众所周知的核糖体脱落现象在蛋白质翻译过程中的翻译准确性和营养饥饿反应中起着至关重要的作用。当细胞处于应激条件下时，例如由于高水平的重组蛋白表达而导致氨基酸饥饿或氨酰基-tRNA耗尽，核糖体脱落会显着影响蛋白表达的效率。在这里，我们介绍了一个数学模型，该模型描述了核糖体脱落对沿 mRNA 的核糖体密度以及伴随的蛋白质合成速率的影响。我们的结果表明，核糖体过早终止可能会导致非直观的核糖体密度分布，例如从 5' 端到 3' 端增加的核糖体密度。重要的是，该模型预测核糖体脱落对翻译率的影响是 mRNA 特异性的，并且我们量化了它们对脱落的恢复力，表明存在核糖体队列的 mRNA 受核糖体脱落的影响比不存在核糖体脱落的 mRNA 要小得多。此外，在那些不存在核糖体队列的 mRNA 中，对脱落的恢复力与延伸率正相关，因此使用快速密码子的序列预计受核糖体脱落的影响较小。这一结果与酿酒酵母的全基因组分析一致，该分析表明，在有利的生长条件下，编码参与翻译机制的蛋白质的 mRNA（已知具有高度密码子偏向性并优先使用快速密码子）对核糖体脱落具有高度弹性。此外，在生理条件下，编码应激相关调节蛋白的 mRNA 的翻译率对核糖体脱落的抵抗力较差。因此，该模型可以通过考虑所有已知核糖体行为来分析单个 mRNA 翻译效率的变化，并解释核糖体分析研究中出现的核糖体密度的 mRNA 特异性变化。核糖体在翻译过程中经常会脱落信使 RNA (mRNA) 分子。这种现象在正常情况下会发生，如果细胞受到压力，这种现象会特别严重。在本文中，我们表明核糖体脱落会强烈影响 mRNA 上的蛋白质生产率和多核糖体谱。它可能导致核糖体密度从 5' 端到 3' 端非直观地增加，以及沿 mRNA 的低核糖体密度和高核糖体密度共存。重要的是，我们表明核糖体脱落的影响是依赖于mRNA的，特定的密码子配置和组成决定了它们对核糖体脱落效应的恢复能力。
The well established phenomenon of ribosome drop-off plays crucial roles in translational accuracy and nutrient starvation responses during protein translation. When cells are under stress conditions, such as amino acid starvation or aminoacyl-tRNA depletion due to a high level of recombinant protein expression, ribosome drop-off can substantially affect the efficiency of protein expression. Here we introduce a mathematical model that describes the effects of ribosome drop-off on the ribosome density along the mRNA and on the concomitant protein synthesis rate. Our results show that ribosome premature termination may lead to non-intuitive ribosome density profiles, such as a ribosome density which increases from the 5’ to the 3’ end. Importantly, the model predicts that the effects of ribosome drop-off on the translation rate are mRNA-specific, and we quantify their resilience to drop-off, showing that the mRNAs which present ribosome queues are much less affected by ribosome drop-off than those which do not. Moreover, among those mRNAs that do not present ribosome queues, resilience to drop-off correlates positively with the elongation rate, so that sequences using fast codons are expected to be less affected by ribosome drop-off. This result is consistent with a genome-wide analysis of S. cerevisiae, which reveals that under favourable growth conditions mRNAs coding for proteins involved in the translation machinery, known to be highly codon biased and using preferentially fast codons, are highly resilient to ribosome drop-off. Moreover, in physiological conditions, the translation rate of mRNAs coding for regulatory, stress-related proteins, is less resilient to ribosome drop-off. This model therefore allows analysis of variations in the translational efficiency of individual mRNAs by accounting for the full range of known ribosome behaviours, as well as explaining mRNA-specific variations in ribosome density emerging from ribosome profiling studies. Ribosomes often drop off the messenger RNA (mRNA) molecules during the process of translation. This phenomenon occurs under normal conditions and it is especially aggravated if the cell is subject to stress. In this paper we show that protein production rates and polysome profiles along the mRNA can be strongly affected by ribosome drop-off. It can lead to a non-intuitive increasing ribosome density profile from the 5’ to 3’ end, as well as coexistence between low and high ribosomal density along the mRNA. Importantly, we show that the repercussions of ribosome drop-off are mRNA-dependent, with the specific codon configuration and composition determining their resilience to ribosome drop-off effects.