Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization

Gillen, S. L., Giacomelli, C., Hodge, K., Zanivan, S. , Bushell, M. and Wilczynska, A. (2021) Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization. Genome Biology, 22, 284. (doi: 10.1186/s13059-021-02494-w) (PMID:34615539) (PMCID:PMC8496106)

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Abstract

Background: 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. Results: 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. Conclusions: 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gillen, Miss Sarah and Zanivan, Professor Sara and Bushell, Professor Martin and Wilczynska, Dr Ania
Authors: Gillen, S. L., Giacomelli, C., Hodge, K., Zanivan, S., Bushell, M., and Wilczynska, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Genome Biology
Publisher:BioMed Central
ISSN:1474-760X
ISSN (Online):1474-760X
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Genome Biology 22:284
Publisher Policy:Reproduced under a Creative Commons licence

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