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Mapping CCR4-NOT recruitment elements at high resolution reveals transcriptome-wide determinants of mRNA decay [RIP-Seq]

ABSTRACT: The CCR4-NOT complex is a central regulator of gene expression, orchestrating mRNA destabilization and decay through interactions with RNA-binding proteins (RBPs) and the miRNA-induced silencing complex (miRISC). However, identifying which RBP and miRNA target sites actively recruit this complex to engender mRNA turnover remains challenging, due in part to the multiple modes by which the CCR4-NOT can be recruited to targets. Here, to address this, we developed TRACER (Targeted RNA Association of CCR4-NOT and Element Recovery), a crosslinking approach that enables high-throughput mapping of cis-acting RNA elements that recruit the CCR4-NOT complex to target RNAs. TRACER analysis of a human epithelial cell line uncovers thousands of CCR4-NOT target elements, including many of which map to known and/or predicted RBP binding motifs, as well as miRNA target sites. Importantly, we show that CCR4-NOT recruitment elements identified by TRACER play important roles in promoting mRNA decay. Taken together, our approach provides the first high-resolution transcriptome-wide map of CCR4-NOT targeting elements in human cells that engender mRNA decay.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302648 | GEO | 2026/04/13

REPOSITORIES: GEO

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Mapping CCR4-NOT recruitment elements at high resolution reveals transcriptome-wide determinants of mRNA decay [miRNA-Seq]

Project description:The CCR4-NOT complex is a central regulator of gene expression, orchestrating mRNA destabilization and decay through interactions with RNA-binding proteins (RBPs) and the miRNA-induced silencing complex (miRISC). However, identifying which RBP and miRNA target sites actively recruit this complex to engender mRNA turnover remains challenging, due in part to the multiple modes by which the CCR4-NOT can be recruited to targets. Here, to address this, we developed TRACER (Targeted RNA Association of CCR4-NOT and Element Recovery), a crosslinking approach that enables high-throughput mapping of cis-acting RNA elements that recruit the CCR4-NOT complex to target RNAs. TRACER analysis of a human epithelial cell line uncovers thousands of CCR4-NOT target elements, including many of which map to known and/or predicted RBP binding motifs, as well as miRNA target sites. Importantly, we show that CCR4-NOT recruitment elements identified by TRACER play important roles in promoting mRNA decay. Taken together, our approach provides the first high-resolution transcriptome-wide map of CCR4-NOT targeting elements in human cells that engender mRNA decay.

2026-04-13 | GSE302649 | GEO

Multivalent Interactions with CCR4-NOT and PABPC1 Determine mRNA Repression Efficiency by Tristetraprolin

Project description:Tristetraprolin family of proteins regulate mRNA stability by binding to specific AU-rich elements in transcripts. This binding promotes the shortening of the mRNA poly(A) tail, or deadenylation, initiating mRNA degradation. The CCR4-NOT complex plays a central role in deadenylation, while the cytoplasmic poly(A)-binding protein PABPC1 typically protects mRNAs from decay. Here, we investigate how tristetraprolin interacts with CCR4-NOT and PABPC1 to control mRNA stability. Using purified proteins and in vitro assays, we find that tristetraprolin engages CCR4-NOT through multiple interaction sites and promotes its activity, emphasizing the importance of multivalent binding for efficient deadenylation. Phosphorylation of tristetraprolin does not affect its interaction with CCR4-NOT or its deadenylation activity, but is essential for tristetraprolin binding to PABPC1. We propose that tristetraprolin promotes the processive deadenylation activity of CCR4-NOT on mRNAs containing AU-rich elements, with phosphorylation-dependent interactions with PABPC1 potentially enhancing deadenylation and promoting regulated mRNA decay.

2025-06-30 | MSV000098386 | MassIVE

UPF1/SMG7-dependent MicroRNA-mediated Gene Regulation

Project description:A majority of metazoan mRNAs are under microRNA (miRNA)/Argonaute (Ago)-mediated control of RNA stability at the post-transcriptional level. Although the molecular mechanism of the miRNA-mediated repression of target mRNAs through Ago/TNRC6 pathway have been largely elucidated, however, the existence of alternative TNRC6-independent miRNA-mediated post-transcriptional gene regulation pathway remains unknown. Here, we suggest that endogenous miRNAs (endo-miRNAs) can downregulate the target mRNAs via the alternative molecular pathway, Ago-associated UPF1/SMG7, core mediators of nonsense-mediated mRNA decay. Global analyses of mRNAs in a response to UPF1 RNA interference in miRNA-deficient cells reveal that 3’UTR-length-dependent mRNA decay by UPF1 requires endo-miRNA targeting via CUG motif. The repression of miRNA targets is more additively or synergistically accomplished by combination of Ago2 and UPF1 through UPF1-associated SMG7, recruiting CCR4-NOT deadenylase complex, in TNRC6-independent manner. We expect that the new miRNA-mediated mRNA decay pathway enables the miRNA targeting to become more predictable and expand the miRNA-mRNA regulatory network.

2019-06-30 | GSE99169 | GEO

Interactome of Nematostella GW182 in HEK293 cells

Project description:Here, we dissect the function of GW182 protein in the cnidarian Nematostella, separated by 600 million years from other Metazoa. Using cultured human cells, we show that Nematostella GW182 recruits the CCR4-NOT deadenylation complexes via its tryptophan-containing motifs, thereby inhibiting translation and promoting mRNA decay. Further, similarly to bilaterians, GW182 in Nematostella is recruited to the miRNA repression complex via interaction with Argonaute proteins, and functions downstream to repress mRNA. Thus, our work suggests that this mechanism of miRNA-mediated silencing was already active in the last common ancestor of Cnidaria and Bilateria. Despite this remarkable mechanistic conservation Argonaute and GW182 differentially co-evolved in bilaterians and cnidarians seemingly leading to distinct interaction surfaces.

2017-03-29 | MSV000080764 | MassIVE

Interactome of Nematostella GW182 in HEK293 cells

2016-09-27 | PXD004668 | Pride

Genome-wide mapping of decay factor-mRNA interactions in yeast identifies nutrient responsive transcripts as targets of the deadenylase Ccr4

Project description:The Ccr4-Not complex is a major regulator of stress responses that controls gene expression at multiple levels, from transcription to mRNA decay. Ccr4, a core subunit of the complex, is the main cytoplasmic deadenylase in Saccharomyces cerevisiae, however its mRNA targets have not been mapped on a genome-wide scale. Here we describe a genome-wide approach, RNA immunoprecipitation-high throughput sequencing (RIP-seq), to identify the RNAs bound to Ccr4, and two proteins that associate with it, Dhh1 and Puf5. All three proteins were preferentially bound to lowly abundant mRNAs, most often at the 3’ end of the transcript. Furthermore, Ccr4, Dhh1 and Puf5 are recruited to mRNAs that are targeted by other RNA-binding proteins that promote decay, mRNA transport and inhibit translation. Although Ccr4-Not regulates mRNA transcription and decay, Ccr4 recruitment to mRNAs correlates better with decay rates, suggesting it imparts greater control over transcript abundance through decay. Ccr4-enriched mRNAs are refractory to control by the other deadenylase complex in yeast, Pan2/3, suggesting a division of labor between these deadenylation complexes. Finally, Ccr4 and Dhh1 associate with mRNAs whose abundance increases during nutrient starvation and those that fluctuate during metabolic and oxygen consumption cycles, which explains the known genetic connections between these factors and nutrient utilization and stress pathways.

2017-12-04 | GSE72366 | GEO

RIP-CHIP data from CNOT6L WT and KO hepatocytes

Project description:mRNA poly(A) tail plays a key role in post-transcriptional regulation of gene expression, including mRNA decay and translation. Deadenylation is a rate-limiting step in mRNA decay, which is catalyzed by the CCR4-NOT complex. To identify mRNAs associated with the CCR4-NOT complex, we have done RIP-CHIP (RNA-immunoprecipitation followed by DNA microarray) using primary hepatocytes from CNOT6L wild-type and knockout mice.

2019-03-29 | GSE62365 | GEO

Examination of mRNA decay rate in mouse embryonic fibroblasts

Project description:The CCR4-NOT dedadenylase complex is essential for mRNA decay and various biological events.To understand roles of the complex in mouse embryonic fibroblasts, we compared mRNA half-lives between control and Cnot complex-deficient mouse embryonic fibroblasts

2020-01-29 | E-MTAB-8287 | biostudies-arrayexpress

Examination of mRNA decay rate in mature adipocytes

Project description:The CCR4-NOT deadenylase complex has a critical function to trigger mRNA decay and various biological events. To understand roles of the complex in adipocyte function, we compare mRNA half-lives between control and Cnot complex-deficient mature adipocytes from iWAT and BAT.

2019-10-24 | E-MTAB-8371 | biostudies-arrayexpress

Interrogating the interaction of fission yeast RNA-binding protein Puf3 with the Ccr4-Not complex using crosslinking mass spectrometry

Project description:mRNA decay is a key determinant of gene regulation, initiated by the shortening of mRNA poly(A) tails by the CCR4-NOT deadenylation complex. Specificity is achieved through RNA adaptors—RNA-binding proteins that recruit CCR4-NOT to specific substrate mRNAs in a regulated manner. However, the molecular mechanisms underlying this specificity remain unclear in many cases. In this study, we applied crosslinking MS to investigate the interaction between the fission yeast RNA-binding protein Puf3 and the Ccr4-Not complex.

2025-09-03 | PXD055147 | Pride

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