Differential regulation of mRNA fate by the human Ccr4-Not complex is driven by coding sequence composition and mRNA localization.
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
06 10 2021
06 10 2021
Historique:
received:
29
10
2020
accepted:
10
09
2021
entrez:
7
10
2021
pubmed:
8
10
2021
medline:
29
1
2022
Statut:
epublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 34615539
doi: 10.1186/s13059-021-02494-w
pii: 10.1186/s13059-021-02494-w
pmc: PMC8496106
doi:
Substances chimiques
CNOT1 protein, human
0
Codon
0
Nuclear Proteins
0
RNA, Messenger
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
284Subventions
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A31287
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/N017005/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29252
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_A600_1024
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M001865/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_G0902052
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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