Abstract
The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. In the nucleus, it is involved in the regulation of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, nuclear RNA surveillance, and DNA damage repair. In the cytoplasm, the Ccr4–Not complex plays a central role in mRNA decay and affects protein quality control. Most of our original knowledge of the Ccr4–Not complex is derived, primarily, from studies in yeast. More recent studies have shown that the mammalian complex has a comparable structure and similar properties. In this review, we summarize the evidence for the multiple roles of both the yeast and mammalian Ccr4–Not complexes, highlighting their similarities.
Highlights
The yeast carbon catabolite repression 4 (Ccr4)–negative on TATA-less (Not) complex is a large (1.9-MDa) and highly conserved multifunctional assembly of proteins, involved in different aspects of mRNA metabolism
Targeted mRNA decay is the best-established function of the Ccr4–Not complex and this plays a key role in post-transcriptional gene silencing by its targeted recruitment to the 30 untranslated regions (UTRs) of mRNAs
The Ccr4–Not complex may function as an effector of the Ras/cAMP pathway that negatively controls the transcription from stress-regulated promoters, by preventing activation of transcription factor Msn2 [159,341]
Summary
The yeast Ccr4–Not complex is a large (1.9-MDa) and highly conserved multifunctional assembly of proteins, involved in different aspects of mRNA metabolism. Targeted mRNA decay is the best-established function of the Ccr4–Not complex and this plays a key role in post-transcriptional gene silencing by its targeted recruitment to the 30 untranslated regions (UTRs) of mRNAs. Genetic evidence shows that RNA-binding proteins (RBPs) and microRNAs have the ability to tether the Ccr4–Not complex to specific sequences at the 30 end of the mRNA, thereby promoting poly (A) shortening and repressing translation and/or mRNA turnover [90]. CNOT1, through its MIF4G domain, binds to the C-terminal RecA domain of the DEAD-box of the RBP protein, DDX6, a central component of translational repression and decapping It stimulates the DDX6 RNA helicase/ATPase and its recruitment to miRNA-targeted mRNAs [34,45]. This may suggest that the level of ubiquitylation activity of Not is regulated by the CNOT holocomplex [134]
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