Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA855935 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19981800_1.fastq.gz | Fastqsanger.gz | |||
| SRR19981800_2.fastq.gz | Fastqsanger.gz | |||
| SRR19981801_1.fastq.gz | Fastqsanger.gz | |||
| SRR19981801_2.fastq.gz | Fastqsanger.gz | |||
| SRR19981802_1.fastq.gz | Fastqsanger.gz |
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Project description:The RNA decapping scavenger, DcpS, has recently been identified as a dependency in acute myeloid leukemia. The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by modulation of DcpS. Considering this strong dependence of AML cell lines on DcpS, we wanted to explore PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, the first PROTAC capable of degrading an mRNA-decapping enzyme. JCS-1 non-covalently binds DcpS with an RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sustained DcpS degradation in several AML cell lines. JCS-1 will serve as a chemical biology tool to interrogate DcpS function in different cellular contexts and may be an applicable strategy for the treatment of AML and other DcpS-dependent genetic disorders.
2022-07-08 | GSE207500 | GEO
Project description:The Dcp2 and Nudt16 Nudix hydrolases, are mRNA decapping enzymes that preferentially modulate stability of a subset of mRNAs. Here we report Nudt3 is a third Nudix protein that possess mRNA decapping activity in cells and is a modulator of cell migration in MCF-7 breast cancer cells. Genome-wide analysis of Nudt3 compromised cells identified increases in mRNAs involved in cell motility including integrin β6, lipocalin-2 and fibronectin. The increase in mRNA levels was dependent on Nudt3 decapping activity where integrin β6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 depleted cells was mediated through the extracellular integrin β6 and fibronectin protein nexus. We conclude, Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals. Stably transformed MCF-7 cell lines constitutively expressing either a short hairpin RNA (shRNA) directed against Nudt3 (Nudt3KD) or a non-targeted control shRNA (ConKD) were used, with three replicate cultures used per group (n=3).
2016-07-21 | E-GEOD-75146 | biostudies-arrayexpress
Project description:Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit the target and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. The oral route of administration is the option of choice in the clinic, but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4 deficient cancers. Here we outline structure- and property-guided approaches that led to the first orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
2022-06-20 | PXD032239 | Pride
Project description:The Dcp2 and Nudt16 Nudix hydrolases, are mRNA decapping enzymes that preferentially modulate stability of a subset of mRNAs. Here we report Nudt3 is a third Nudix protein that possess mRNA decapping activity in cells and is a modulator of cell migration in MCF-7 breast cancer cells. Genome-wide analysis of Nudt3 compromised cells identified increases in mRNAs involved in cell motility including integrin β6, lipocalin-2 and fibronectin. The increase in mRNA levels was dependent on Nudt3 decapping activity where integrin β6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 depleted cells was mediated through the extracellular integrin β6 and fibronectin protein nexus. We conclude, Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals.
2016-07-21 | GSE75146 | GEO
Project description:The decapping scavenger enzyme DcpS is known for its role in hydrolyzing the cap structure following mRNA degradation. Recently, we discovered a new function in miRNA degradation activation for the ortholog of DcpS in C. elegans. Here we show that human DcpS conserves its role in miRNA turnover. In human cells, DcpS is a nucleocytoplasmic shuttling protein and that DcpS activates miRNA degradation independently of its scavenger decapping activity in the cytoplasmic compartment. We also demonstrate that this new function for DcpS requires the contribution of the 5’-3’ exonuclease Xrn2. Our findings support a conserved role of DcpS as a modulator of miRNA turnover in animals.
2016-05-23 | GSE69591 | GEO
Project description:Homozygous mutations in the gene encoding the scavenger mRNA-decapping enzyme, DcpS, have been shown to underlie developmental delay and intellectual disability. Intellectual disability is associated with both abnormal neocortical development and mRNA metabolism. However, the role of DcpS and its scavenger decapping activity in proper neuronal development is unknown. Here, we show that differentiation of human induced pluripotent stem cell derived neurons, from patients with a DcpS mutation, are impaired and have compromised neurite outgrowth. Moreover, misexpression of DcpS in developing mouse neocortex revealed that DcpS is required for the multipolar morphology acquisition, neurite outgrowth and identity of developing neocortical glutamatergic neurons in the mouse brain. Collectively, these findings demonstrate the scavenger mRNA decapping activity contributes to multiple pivotal roles in neurodevelopment, and further corroborate that mRNA metabolism and neocortical pathologies are associated with intellectual disability.
2022-04-06 | GSE173603 | GEO
Project description:Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over small molecule inhibitors. We describe dTAGV-1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12F36V-tagged proteins. dTAGV-1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice
2020-09-21 | PXD018937 | Pride
Project description:We report the application of next generation sequencing for measurement of mRNA levels under the effect of a macrocyclic inhibtor of human decapping enzyme 2 (hDcp2).
2018-05-23 | GSE114781 | GEO
Project description:mRNA-decapping associated DcpS enzyme controls critical steps of neuronal development
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Project description:Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
| S-EPMC9551036 | biostudies-literature