MRNA-decapping associated DcpS enzyme controls critical steps of neuronal development
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ABSTRACT:
PROVIDER: PRJNA726245 | ENA |
REPOSITORIES: ENA
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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: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: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: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: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:Targeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC
| PRJNA855935 | ENA
Project description:Removal of mRNA 5’ caps primes transcripts for degradation and is central for regulating gene expression in eukaryotes. The canonical decapping enzyme DCP2 is stringently controlled by assembly into a dynamic multi-protein complex together with the 5´-3´exoribonuclease Xrn1. Kinetoplastida lack DCP2 orthologues but instead rely on the ApaH-like phosphatase ALPH1 for decapping. The enzyme is composed of a catalytic domain flanked by C-terminal and N-terminal extensions. In our related deposition PXD038550 we analysed the ALPH1 interactome by BioID proximity labelling for the full length protein and truncated versions in order to assign domain specific interactions. We showed that Trypanosoma brucei ALPH1 acts in a complex composed of the trypanosome XRN1 ortholog XRNA and four proteins that are unique to Kinetoplastida. The interactome was validated by reverse experiments targeting T. brucei and T. cruzi XRNA by affinity capture and, additionally, the ALPH1 interacting CMGC-family kinase by BioID. Here we carried out affinity capture with T. brucei and T. cruzi ALPH1, which delivers a potential sub-complex missing the C-terminal interactor XRNA.
2023-06-14 | PXD042322 | Pride
Project description:Decapping enzyme NUDT12 partners with BLMH for cytoplasmic surveillance of NAD-capped RNAs
| PRJNA574161 | ENA
Project description:Human tumors show aberrant RNA profiles that can originate from multiple pathways and mechanisms. One underexplored area is that alterations in RNA decapping, the addition of a 5´-end N7-methyl guanosine (m7G)-cap that is essential for stabilization of the RNA molecule, could also be involved in the distorted transcript landscape of cancer cells. Herein we show that the RNA editing enzyme NUDT16 undergoes promoter CpG island methylation-associated silencing in T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples. The restoration of in vitro and in vivo NUDT16 activity highlights the growth inhibitory features of the gene. Most importantly, we identify that the epigenetic loss of NUDT16 in leukemia cells prevents the RNA decay of growth-promoting genes, among them the C-MYC stabilizers FBXO28 and USP37, leading to higher levels of the oncogenic protein.
2017-04-06 | GSE84973 | GEO