Regulation of protein output at the level of translation allows for a rapid adaptation to dynamic changes to the cell’s requirements. This precise control of gene expression is achieved by complex and interlinked biochemical processes that modulate both the protein synthesis rate and stability of each individual mRNA. A major factor coordinating this regulation is the Ccr4-Not complex. Despite playing a role in most stages of the mRNA life cycle, no attempt has been made to take a global integrated view of how the Ccr4-Not complex affects gene expression. This study has taken a comprehensive approach to investigate post-transcriptional regulation mediated by the Ccr4-Not complex assessing steady-state mRNA levels, ribosome position, mRNA stability, and protein production transcriptome-wide. Depletion of the scaffold protein CNOT1 results in a global upregulation of mRNA stability and the preferential stabilization of mRNAs enriched for G/C-ending codons. We also uncover that mRNAs targeted to the ER for their translation have reduced translational efficiency when CNOT1 is depleted, specifically downstream of the signal sequence cleavage site. In contrast, translationally upregulated mRNAs are normally localized in p-bodies, contain disorder-promoting amino acids, and encode nuclear localized proteins. Finally, we identify ribosome pause sites that are resolved or induced by the depletion of CNOT1. We define the key mRNA features that determine how the human Ccr4-Not complex differentially regulates mRNA fate and protein synthesis through a mechanism linked to codon composition, amino acid usage, and mRNA localization.

中文翻译：

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人类 Ccr4-Not 复合物对 mRNA 命运的差异调节是由编码序列组成和 mRNA 定位驱动的

在翻译水平上调节蛋白质输出可以快速适应细胞需求的动态变化。这种对基因表达的精确控制是通过复杂且相互关联的生化过程来实现的，这些过程调节蛋白质合成速率和每个单独 mRNA 的稳定性。协调该调节的一个主要因素是 Ccr4-Not 复合体。尽管在 mRNA 生命周期的大多数阶段发挥着作用，但尚未尝试对 Ccr4-Not 复合物如何影响基因表达进行整体综合观察。本研究采用综合方法来研究 Ccr4-Not 复合体介导的转录后调控，评估稳态 mRNA 水平、核糖体位置、mRNA 稳定性和转录组范围内的蛋白质产生。支架蛋白 CNOT1 的耗尽会导致 mRNA 稳定性的整体上调以及富含 G/C 结尾密码子的 mRNA 的优先稳定。我们还发现，当 CNOT1 耗尽时，针对 ER 进行翻译的 mRNA 的翻译效率会降低，特别是在信号序列切割位点的下游。相反，翻译上调的 mRNA 通常位于 p 体中，含有促进紊乱的氨基酸，并编码核定位蛋白。最后，我们确定了因 CNOT1 耗尽而被解析或诱导的核糖体暂停位点。我们定义了决定人类 Ccr4-Not 复合物如何通过与密码子组成、氨基酸使用和 mRNA 定位相关的机制差异调节 mRNA 命运和蛋白质合成的关键 mRNA 特征。