In humans, the Ccr4-Not complex has a molecular weight of ~ 1.2 MDa. It is a major complex involved in regulating an mRNA throughout the entire mRNA life cycle including facilitating mRNA export, co-translational assembly of protein complexes, translational repression, deadenylation, and mRNA destabilization. It has since been shown to have key regulatory roles extending well beyond transcription. The Ccr4-Not complex is a large evolutionarily conserved multi-protein complex, first described as a regulator of transcription. 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. Finally, we identify ribosome pause sites that are resolved or induced by the depletion of CNOT1. In contrast, translationally upregulated mRNAs are normally localized in p-bodies, contain disorder-promoting amino acids, and encode nuclear localized proteins. 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. 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. 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. 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.
A major factor coordinating this regulation is the Ccr4-Not complex. 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. Regulation of protein output at the level of translation allows for a rapid adaptation to dynamic changes to the cell’s requirements.
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