Abstract:Regulation of RNA stability plays a crucial role in gene expression control. Deadenylation is the initial rate-limiting step for the majority of RNA decay events. Here, we show that RING finger protein 219 (RNF219) interacts with the CCR4‒NOT deadenylase complex. RNF219‒CCR4‒NOT exhibits deadenylation activity in vitro. RNA-seq analyses identify some of the 2-cell-specific genes and the neuronal genes significantly downregulated upon RNF219 knockdown, while upregulated after depletion of the CCR4‒NOT subunit C… Show more
“…Of note, we observed robust peptide coverage measured for the different CCR4-NOT deadenylase subunits CNOT6, CNOT6L, CNOT7 and CNOT8, suggesting that RNF219 can stably associate with CCR4-NOT complexes containing either subunit. Our finding is consistent with a recent studies, which independently describe the interaction between RNF219 and CCR4-NOT 32 , 33 . Figure 2 RNF219 binds to the CCR4-NOT complex.…”
Section: Resultssupporting
confidence: 94%
“…We further show that RNF219 inhibits the translation and stabilizes the poly(A) tail of a reporter mRNA. During the course of our study two groups independently reported RNF219 association with human CCR4-NOT, negatively affecting its enzymatic function 32 , 33 . Importantly, loss of the interaction between RNF219 and the CCR4-NOT complex abolishes these two activities.…”
Section: Introductionmentioning
confidence: 81%
“…7 ). During the course of our study, two laboratories provided independent evidence that RNF219 associates with the human CCR4-NOT complex and negatively regulates deadenylation 32 , 33 .…”
Post-transcriptional regulatory mechanisms play a role in many biological contexts through the control of mRNA degradation, translation and localization. Here, we show that the RING finger protein RNF219 co-purifies with the CCR4-NOT complex, the major mRNA deadenylase in eukaryotes, which mediates translational repression in both a deadenylase activity-dependent and -independent manner. Strikingly, RNF219 both inhibits the deadenylase activity of CCR4-NOT and enhances its capacity to repress translation of a target mRNA. We propose that the interaction of RNF219 with the CCR4-NOT complex directs the translational repressive activity of CCR4-NOT to a deadenylation-independent mechanism.
“…Of note, we observed robust peptide coverage measured for the different CCR4-NOT deadenylase subunits CNOT6, CNOT6L, CNOT7 and CNOT8, suggesting that RNF219 can stably associate with CCR4-NOT complexes containing either subunit. Our finding is consistent with a recent studies, which independently describe the interaction between RNF219 and CCR4-NOT 32 , 33 . Figure 2 RNF219 binds to the CCR4-NOT complex.…”
Section: Resultssupporting
confidence: 94%
“…We further show that RNF219 inhibits the translation and stabilizes the poly(A) tail of a reporter mRNA. During the course of our study two groups independently reported RNF219 association with human CCR4-NOT, negatively affecting its enzymatic function 32 , 33 . Importantly, loss of the interaction between RNF219 and the CCR4-NOT complex abolishes these two activities.…”
Section: Introductionmentioning
confidence: 81%
“…7 ). During the course of our study, two laboratories provided independent evidence that RNF219 associates with the human CCR4-NOT complex and negatively regulates deadenylation 32 , 33 .…”
Post-transcriptional regulatory mechanisms play a role in many biological contexts through the control of mRNA degradation, translation and localization. Here, we show that the RING finger protein RNF219 co-purifies with the CCR4-NOT complex, the major mRNA deadenylase in eukaryotes, which mediates translational repression in both a deadenylase activity-dependent and -independent manner. Strikingly, RNF219 both inhibits the deadenylase activity of CCR4-NOT and enhances its capacity to repress translation of a target mRNA. We propose that the interaction of RNF219 with the CCR4-NOT complex directs the translational repressive activity of CCR4-NOT to a deadenylation-independent mechanism.
“… 32 In mouse embryonic stem cells, depletion of CNOT10 was shown to promote the accumulation of specific transcripts. 33 Finally, in trypanosoma, deletion of the CNOT10 orthologue impaired the integrity of the CCR4-NOT complex, and consequently the degradation of many mRNAs. 34 Altogether, the precise organization and functions of the CNOT1 N -CNOT10-CNOT11 module remain enigmatic.…”
“…In this case, the interaction region of GGNBP2 comprises approximately 32 amino acids, which form two α-helices that wrap around the HEAT repeats of the C-terminal region of CNOT11 ( Mauxion et al, 2022 ). Because knockdown of CNOT10 in mouse ES cells results in upregulation of a large number of mRNAs ( Du et al, 2020 ), it is tempting to speculate that recruitment of Ccr4-Not via the N-terminal module can serve as a mechanism for the regulation of mRNA levels ( Mauxion et al, 2022 ).…”
Section: Regulation Of Mrna Deadenylation By Sequence Elements In 3’ Utrmentioning
Accurate and precise regulation of gene expression programmes in eukaryotes involves the coordinated control of transcription, mRNA stability and translation. In recent years, significant progress has been made about the role of sequence elements in the 3′ untranslated region for the regulation of mRNA degradation, and a model has emerged in which recruitment of the Ccr4-Not complex is the critical step in the regulation of mRNA decay. Recruitment of the Ccr4-Not complex to a target mRNA results in deadenylation mediated by the Caf1 and Ccr4 catalytic subunits of the complex. Following deadenylation, the 5′ cap structure is removed, and the mRNA subjected to 5′-3′ degradation. Here, the role of the human Ccr4-Not complex in cytoplasmic deadenylation of mRNA is reviewed, with a particular focus on mechanisms of its recruitment to mRNA by sequence motifs in the 3′ untranslated region, codon usage, as well as general mechanisms involving the poly(A) tail.
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