A hotspot mutation targeting the R-RAS2 GTPase acts as a potent oncogenic driver in a wide spectrum of tumors
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PROVIDER: PRJNA743644 | ENA |
REPOSITORIES: ENA
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Project description:A missense change in RRAS2 (Gln72-to-Leu), analogous to the Gln61-to-Leu mutation of RAS oncoproteins, has been identified as a hotspot mutation in cancer and Noonan syndrome. However, the relevance of this mutation for in vivo tumorigenesis remains unknown. Here, we show that R-RAS2(Q72L) is required for optimal tumorigenic activity of human cancer cells.
2022-03-04 | GSE179409 | GEO
Project description:The R-RAS2 GTPase has been considered quite similar to classical RAS proteins at the regulatory, signaling, and functional level. The interest in this GTPase has been reinvigorated upon the recent discovery that a long-tail hotspot RRAS2 mutation found in human tumors (Gln72 to Leu) can act as a potent oncogenic driver. Here, we report that the Q72L mutation and other gain-of-function mutations of RRAS2 play roles in tumor initiation and maintenance. Such roles are unlikely to be redundant to those normally executed by classical RAS proteins.
2022-12-03 | GSE201472 | GEO
Project description:Recurrent somatic hotspot mutations of DICER1 appear to be clustered around each of four critical metal binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3’ end of the 5p-miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated “hotspot” mutations we engineered mouse Dicer1-deficient ES cells to express wild-type and an allelic series of the mutant human DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal binding site mutations were compared to each other and wild-type human DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation carrying cells were distinct from both wild-type and Dicer1-deficient cells. Further, miRNA profiles showed mutant DICER1 results in a dramatic loss in processing of mature 5p-miRNA strands but were still able to create 3p-strand miRNAs. Messenger-RNA profile changes were consistent with the loss of 5p-strand miRNAs and showed enriched expression for predicted targets of the lost 5p derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA-processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p-strand miRNA. We further propose that this resulting 3p-strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. A total of 28 Affymetrix Mouse Gene ST arrays were done for mRNA expression profiling of various DICER1 mutants (n=14), wildtype controls (n=6), vector only (n=3) and parental cell lines (n=5).
2012-10-01 | E-GEOD-40965 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE24749: Rap1a GTPase mVSM Knockout vs. Rescue miRNA Expression GSE25702: Rap1a GTPase mVSM Knockout vs. Rescue mRNA Expression Refer to individual Series
2011-04-13 | E-GEOD-25703 | biostudies-arrayexpress
Project description:IKZF3 encodes an IKAROS Family transcription factor and has been recently identified as a novel mutated gene in chronic lymphocytic leukemia (CLL), with all mutations occurring at a single hotspot (L162R), located within the DNA binding domain of the protein. Here we show that B cell-restricted conditional knock-in of this mutation skews B cells development and induces CLL-like disease in elderly mice (30% penetrance), confirming its role as a CLL driver. Furthermore, this mutation alters the DNA binding specificity and target selection of IKZ3, leading to overexpression of BCR/NF-?B signaling genes and hyperactivation of these pathways. Likewise, we find an upregulated BCR signaling signature in human CLLs with IKZF3-L162R. Our studies highlight a novel mechanism by which a CLL driver activates the critical oncogenic BCR/NF-?B signaling axis in CLL
2020-12-01 | GSE143711 | GEO
Project description:Recurrent somatic hotspot mutations of DICER1 appear to be clustered around each of four critical metal binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3’ end of the 5p-miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated “hotspot” mutations we engineered mouse Dicer1-deficient ES cells to express wild-type and an allelic series of the mutant human DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal binding site mutations were compared to each other and wild-type human DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation carrying cells were distinct from both wild-type and Dicer1-deficient cells. Further, miRNA profiles showed mutant DICER1 results in a dramatic loss in processing of mature 5p-miRNA strands but were still able to create 3p-strand miRNAs. Messenger-RNA profile changes were consistent with the loss of 5p-strand miRNAs and showed enriched expression for predicted targets of the lost 5p derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA-processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p-strand miRNA. We further propose that this resulting 3p-strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations.
2012-10-01 | GSE40965 | GEO
Project description:High-throughput Discovery of Functional Protein Modifications by Hotspot Thermal Profiling
2019-05-16 | MSV000083786 | MassIVE
Project description:DICER1 plays a critical role in microRNA (miRNA) biogenesis. Recurrent somatic “hotspot” mutations at four mental binding sites within the RNase IIIb domain of DICER1, were identified in ovarian sex cord-stromal tumors and have since been described in other pediatric tumors. In this study, we identified and characterized DICER1 hotspot mutations in endometrial cancers derived from The Cancer Genome Atlas (TCGA) and our local tumor bank. DICER1 hotspot mutations are found in ~2% of endometrial tumors. Using Illumina and Sanger targeted resequencing we observed biallelic DICER1 mutations in more than 50% of cases with hotspot mutations and identified an additional recurrent mutation G1809R in 2 cases. Through small RNA deep sequencing and real-time PCR, we demonstrated mutations that add a positively charged side chain to residue 1809 have similar detrimental effects on 5p miRNA production as mutations at metal binding sites. In one case G1809R was compound heterozygous with a germline S839F mutation, which contributes to loss of DICER1 expression by promoting protein degradation. As expected, 5p miRNAs are globally reduced in tumors and cell lines with hotspot mutations. Pathway analysis of gene expression profiles indicated that genes derepressed due to loss of 5p miRNAs are strongly associated with cell cycle related pathways. Using a Dicer null cell line model, we demonstrated that DICER1 hotspot mutants abolished the inhibitory effects of wildtype DICER1 on cell proliferation upon re-expression. Furthermore, targets of let-7 family miRNAs are enriched among the upregulated genes, suggesting loss of let-7 may be impacting downstream pathways.
2015-03-16 | GSE65092 | GEO
Project description:Homologous recombination events during meiosis cluster at specific loci called hotspots. Hotspot activation requires accessible chromatin, DNA sequence motifs DNA sequence-specific binding proteins, but how these proteins create a suitable environment for Rec12 recruitment is unknown. Here, we purified the ade6-M26 meiotic recombination hotspot from Schizosaccharomyces pombe and identified novel regulators of hotspot activation by mass spectrometry. Small, circular minichromosomes containing the ade6-M26 hotspot or control allele were transformed into strains permitting synchronous meiotic induction and purified from these cultures at sequential time points. Enrichment of known M26 binding factors Atf1 and Pcr1 in the data set validated the approach. Filtering for chromatin-related proteins enriched in the hotspot revealed candidate hotspot regulators, which were validated using genetic studies. This study highlights the power of unbiased proteomic screens to reveal novel insights into fundamental biological processes, and highlights a critical role in H2AZ turnover in mediating access of transcription factors to their underlying DNA-sequence motifs.
2018-11-04 | PXD009649 | Pride
Project description:Cancer Driver Discovery Program (CDDP)
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