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The CCR4-Not complex is a tumor suppressor in Drosophila melanogaster eye cancer models

ABSTRACT: The CNOT3 protein is a subunit of the CCR4-Not complex, a cytoplasmic protein complex mediating mRNA deadenylation as the first step in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL). However, it is not clear yet how loss of this gene is involved in cancer development. Here we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, as well as other members of the CCR4-NOT complex. We show that not only Not3 but also the structural components Not1 and Not2, as well as the deadenylases Twin and Pop2 all behave as tumor suppressor genes. Moreover, RNA-sequencing analyses revealed that Not3 loss leads to increased expression levels of genes involved in DNA replication and ribosome biogenesis pathways, and that CycB is a Not3 target gene in our cancer models. Furthermore, we were able to confirm those results on human T-ALL cell lines, pointing out the conserved function of Not3 in both model systems and in tumor development. Together, our data establish a critical role for Not3 and the entire CCR4-NOT complex as a tumor suppressor.

ORGANISM(S): Homo sapiens Drosophila melanogaster

PROVIDER: GSE103872 | GEO | 2017/09/15

SECONDARY ACCESSION(S): PRJNA407359

REPOSITORIES: GEO

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Regulation of B cell early development by CNOT3

Project description:The CCR4-NOT complex, bearing poly(A) deadenylation activity, is a highly conserved regulator that is involved in biological control; however its action mechanisms and physiological targets remain unclear. Using genetic deletion of the CNOT3 subunit of this complex in early B cell progenitors, we show that CNOT3 plays a critical role in pro- to pre-B cell transition. CNOT3 participated in controlling germline transcription, compaction of the immunoglobulin heavy chain (Igh) locus, and Igh rearrangement, and in destabilizing tumor suppressor p53 mRNA. Moreover, by genetic ablation of p53 or introduction of pre-rearranged Igh transgene, the B cell developmental defect in the Cnot3 knockout background could be partly rescued, suggesting that CCR4-NOT complex exerts critical control in B cell differentiation processes by co-utilizing transcriptional and post-transcriptional mechanisms. Pro-B cells mRNA profiles of Mb1(cre/+) and Cnot3(fl/fl)Mb1(cre/+) mice were generated by deep sequencing using Illumina HiSeq 1500

2015-07-23 | E-GEOD-64455 | biostudies-arrayexpress

Regulation of B cell early development by CNOT3

2015-07-23 | GSE64455 | GEO

Transcription profiling of S. cerevisiae wild type reference strain, two simple mutants (not1-2 and spt3) and one double mutant (not1-2 spt3) reveals a SAGA-Independent function of SPT3 mediates transcriptional deregulation in a mutant of the Ccr4-Not Complex

Project description:The conserved multi-subunit Ccr4-Not complex regulates gene expression in diverse ways. In this work, we characterize the suppression of temperature sensitivity associated with a mutation in the gene encoding the scaffold subunit of the Ccr4-Not complex, NOT1, by the deletion of SPT3. We determine that the deletion of SPT3, but not the deletion of genes encoding other subunits of the SAGA complex, globally suppresses transcriptional defects of not1-2. We find that transcriptional activation in not1-2 is associated with increased binding of TFIID and SAGA at promoters of upregulated genes, and this is suppressed by the deletion of SPT3. Interestingly, Spt3p-dependent activation of transcription occurs in not1-2 even if the SAGA complex is disrupted by the deletion of SPT7 that encodes a subunit of SAGA required for its integrity. Consistent with a SAGA-independent function of Spt3p, the deletion of SPT3 displays synthetic phenotypes when combined with a deletion of SPT7. Taken together, our results provide a new view of the Spt3 protein by identifying a SAGA-independent function of this protein that is functionally linked to the Ccr4-Not complex. Experiment Overall Design: 4 strains were analyzed: the wild type reference strain, two simple mutants (not1-2 and spt3) and one double mutant (not1-2 spt3). All strains were in duplicate.

2008-06-16 | E-GEOD-9432 | biostudies-arrayexpress

Transcriptome analysis of Arabidopsis mature pollen grains from wild type and heterozygous NOT1 mutants

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RNA-seq of mouse islets from Ins1-cre driven Cnot3 KO and control islets

Project description:The CCR4-NOT dedadenylase complex is essential for mRNA decay and various biological events.To understand roles of the complex in pancreatic beta cells, we compared global gene expression in Ins1-cre driven Cnot3 KO and control islets. Cnot3 is an important subunit of the complex and its knockout affects the complex activity.

2020-08-29 | E-MTAB-8729 | biostudies-arrayexpress

The CCR4-NOT complex component NOT1 regulates RNA-directed DNA methylation and transcriptional silencing by facilitating Pol IV-dependent siRNA production [Bisulfite-seq]

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2020-05-15 | GSE148428 | GEO

The CCR4-NOT complex component NOT1 regulates RNA-directed DNA methylation and transcriptional silencing by facilitating Pol IV-dependent siRNA production [small RNA-seq]

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Expression data from mouse embryonic fibroblasts

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2015-09-01 | E-GEOD-67418 | biostudies-arrayexpress

Expression data from the liver of wild-type and Cnot3+/- mice: Fed vs Fasted

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2011-12-09 | E-GEOD-18925 | biostudies-arrayexpress

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2007-10-26 | GSE9432 | GEO

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