Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization.
Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization.
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人类Ccr4-Not复合物对mRNA命运的差异调控是由编码序列组成和mRNA定位驱动的。
DOI：
10.1186/s13059-021-02494-w
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发表时间：
2021-10-06
期刊：
影响因子：
12.3
通讯作者：
Wilczynska A
中科院分区：
文献类型：
--
作者：
Gillen SL;Giacomelli C;Hodge K;Zanivan S;Bushell M;Wilczynska A
在翻译水平上调节蛋白质输出允许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和相互关联的生化过程来实现的，这些生化过程调节蛋白质合成速率和每个mRNA的稳定性。协调这种调节的一个主要因素是Ccr 4-不复杂。尽管在mRNA生命周期的大多数阶段中发挥作用，但尚未尝试对Ccr 4-Not复合物如何影响基因表达采取全局综合观点。本研究采用了一种全面的方法来研究由Ccr 4-Not复合物介导的转录后调节，评估稳态mRNA水平，核糖体位置，mRNA稳定性和蛋白质产生转录组范围。支架蛋白hocT 1的耗尽导致mRNA稳定性的整体上调和富含G/C末端密码子的mRNA的优先稳定。我们还发现，靶向ER的mRNA的翻译有降低的翻译效率时，hocT 1被耗尽，特别是下游的信号序列切割位点。相反，转录上调的mRNA通常位于p体中，含有促进疾病的氨基酸，并编码核定位蛋白。最后，我们确定了核糖体暂停网站，解决或引起的损耗hocT 1。我们定义了关键的mRNA功能，决定了人类Ccr 4-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。在线版本包含补充材料，可通过10.1186/s13059-021-02494-w获得。
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. The online version contains supplementary material available at 10.1186/s13059-021-02494-w.
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影响因子：
8.8
作者：
Burow DA;Martin S;Quail JF;Alhusaini N;Coller J;Cleary MD
通讯作者：
Cleary MD
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
9.8
作者：
Charneski CA;Hurst LD
通讯作者：
Hurst LD
影响因子：
14.9
作者：
Arvola, Rene M.;Chang, Chung-Te;Goldstrohm, Aaron C.
通讯作者：
Goldstrohm, Aaron C.
影响因子：
7.3
作者：
Chen, Chyi-Ying A.;Shyu, Ann-Bin
通讯作者：
Shyu, Ann-Bin