RNA Biology Laboratory, Department of Biology and CESAM, University of Aveiro, Aveiro, Portugal.
BMC Biol. 2012 Jun 20;10:55. doi: 10.1186/1741-7007-10-55.
Organisms use highly accurate molecular processes to transcribe their genes and a variety of mRNA quality control and ribosome proofreading mechanisms to maintain intact the fidelity of genetic information flow. Despite this, low level gene translational errors induced by mutations and environmental factors cause neurodegeneration and premature death in mice and mitochondrial disorders in humans. Paradoxically, such errors can generate advantageous phenotypic diversity in fungi and bacteria through poorly understood molecular processes.
In order to clarify the biological relevance of gene translational errors we have engineered codon misreading in yeast and used profiling of total and polysome-associated mRNAs, molecular and biochemical tools to characterize the recombinant cells. We demonstrate here that gene translational errors, which have negligible impact on yeast growth rate down-regulate protein synthesis, activate the unfolded protein response and environmental stress response pathways, and down-regulate chaperones linked to ribosomes.
We provide the first global view of transcriptional and post-transcriptional responses to global gene translational errors and we postulate that they cause gradual cell degeneration through synergistic effects of overloading protein quality control systems and deregulation of protein synthesis, but generate adaptive phenotypes in unicellular organisms through activation of stress cross-protection. We conclude that these genome wide gene translational infidelities can be degenerative or adaptive depending on cellular context and physiological condition.
生物利用高度精确的分子过程来转录其基因，并且存在多种 mRNA 质量控制和核糖体校对机制，以维持遗传信息流的完整性和保真度。尽管如此，由突变和环境因素引起的低水平基因翻译错误会导致小鼠的神经退行性变和早逝，以及人类的线粒体疾病。矛盾的是，此类错误可以通过尚未完全理解的分子过程，在真菌和细菌中产生有利的表型多样性。
为了阐明基因翻译错误的生物学相关性，我们在酵母中设计了密码子错读，并使用总 mRNA 和多核糖体相关 mRNA 的分析、分子和生化工具来对重组细胞进行特征描述。我们在此证明，对酵母生长速率几乎没有影响的基因翻译错误会下调蛋白质合成，激活未折叠蛋白反应和环境应激反应途径，并下调与核糖体相关的伴侣分子。
我们提供了对全局基因翻译错误的转录和转录后反应的首次全局视图，并且我们推测它们通过蛋白质质量控制系统过载和蛋白质合成失调的协同作用导致细胞逐渐退化，但通过应激交叉保护的激活，在单细胞生物中产生适应性表型。我们得出的结论是，这些全基因组范围的基因翻译不忠实性可能是退行性的，也可能是适应性的，这取决于细胞环境和生理状况。
