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Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

ABSTRACT: Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

PROVIDER: PRJNA680989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13151200.fastq.gz	Fastqsanger.gz
	SRR13151201.fastq.gz	Fastqsanger.gz
	SRR13151202.fastq.gz	Fastqsanger.gz
	SRR13151203.fastq.gz	Fastqsanger.gz
	SRR13151204.fastq.gz	Fastqsanger.gz

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Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

Project description:Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR/Cas9-based gene-editing studies. We observed that myeloma cell resistance to "degraders" of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; involves loss-of-function for the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for CRBN- vs. VHL-based degraders explains mechanistically the lack of cross-resistance for degraders targeting the same protein via different E3 ligase/CRLs.

2021-02-12 | GSE162205 | GEO

Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.

Project description:Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.

| S-EPMC8485877 | biostudies-literature

Local Genomic Features Predict the Distinct and Overlapping Binding Patterns of the bHLH‐Zip Family Oncoproteins MITF and MYC‐MAX

Project description:MITF and MYC are well‐known oncoproteins and members of the basic helix‐loop‐helix leucine zipper (bHLH‐Zip) family of transcription factors (TFs) recognizing hexamer E‐box motifs. MITF and MYC not only share the core binding motif, but are also the two most highly expressed bHLH‐Zip transcription factors in melanocytes, raising the possibility that they may compete for the same binding sites in select oncogenic targets. Mechanisms determining the distinct and potentially overlapping binding modes of these critical oncoproteins remain uncharacterized. We introduce computational predictive models using local sequence features, including a boosted convolutional decision tree framework, to distinguish MITF vs. MYC‐MAX binding sites with up to 80% accuracy genome wide. Select E‐box locations that can be bound by both MITF and MYC‐MAX form a separate class of MITF binding sites characterized by differential sequence content in the flanking region, diminished interaction with SOX10, higher evolutionary conservation, and less tissue‐specific chromatin organization.

2018-12-14 | GSE115845 | GEO

HCH degraders

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Electron acceptor-dependent identification of key anaerobic toluene degraders at a tar-oil contaminated aquifer by Pyro-SIP

Project description:Bioavailability of electron acceptors is probably the most limiting factor in the restoration of anoxic, contaminated environments. The oxidation of contaminants such as aromatic hydrocarbons, particularly in aquifers, often depends on the reduction of ferric iron or sulphate. We have previously detected a highly active fringe zone beneath a toluene plume at a tar-oil contaminated aquifer in Germany, where a specialized community of contaminant degraders co-dominated by Desulfobulbaceae and Geobacteraceae had established. Although on-site geochemistry links degradation to sulphidogenic processes, dominating catabolic (benzylsuccinate synthase alpha-subunit, bssA) genes detected in situ appeared more related to those of Geobacter spp. Therefore, a stable isotope probing (SIP) incubation of sediment samples with 13C7-toluene and comparative electron acceptor amendment was performed. We introduce pyrosequencing of templates from SIP microcosms as a powerful new strategy in SIP gradient interpretation (Pyro-SIP). Our results reveal the central role of Desulfobulbaceae for sulphidogenic toluene degradation in situ, and affiliate the detected bssA genes to this lineage. This, and the absence of 13C-labelled DNA of Geobacter spp. in SIP gradients preclude their relevance as toluene degraders in situ. In contrast, Betaproteobacteria related to Georgfuchsia spp. became labelled under iron-reducing conditions. Furthermore, secondary toluene degraders belonging to the Peptococcaceae detected in both treatments suggest the possibility of functional redundancy amongst anaerobic toluene degraders on site. 2 samples examined from the different electron-acceptors (sulphate or ferric iron) incubates at the time point of maximal toluene degradation.

2011-03-18 | E-GEOD-25449 | biostudies-arrayexpress

DNA-SIP ETBE degraders

Project description:Stable isotope profiling of ETBE degraders

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Small-molecule degraders of SUMO1 induce the protein ubiquitination and degradation through CAPRIN1-CUL1-FBXO42 ubiquitin ligase for cancer therapySmall-molecule degraders of SUMO1 induce the protein ubiquitination and degradation through CAPRIN1-CUL1-FBXO42 ubiquitin ligase for cancer therapy

Project description:Targeted protein degradation has been a long sought, but elusive, strategy for discovery of small-molecule degraders that activate E3 ubiquitin ligase-mediated ubiquitination and degradation of targeted proteins in cancer cells. Here, we report a cancer cell-based drug screen in the discovery of small-molecule degraders of SUMO1 that has been an otherwise undruggable protein. Genome-scale CRISPR-CAS9 screen combined with compound pulldown proteomics identified the binding partner CAPRIN1 and the SUMO1 substrate receptor FBXO42 of CUL1 E3 ligase. Upon binding of CAPRIN1, SUMO1 degraders induce CAPRIN1-FBXO42 interaction and recruitment of SUMO1 to the CAPRIN1-CUL1-FBXO42 E3 ligase for SUMO1 ubiquitination and degradation in cancer but not normal cells. SUMO1 degraders exhibit drug-like pharmacokinetics and profound anticancer activity against various cancer models. This cancer cell-based drug screen provides an alternative approach for the discovery of new small-molecule degraders of oncoproteins as a new generation of anticancer drugs.

2022-10-13 | PXD022399 | Pride

Polycyclic aromatic hydrocarbons degraders

Project description:Polycyclic aromatic hydrocarbons degraders Raw sequence reads

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Local Genomic Features Predict the Distinct and Overlapping Binding Patterns of the bHLH‐Zip Family Oncoproteins MITF and MYC‐MAX

Project description:Local Genomic Features Predict the Distinct and Overlapping Binding Patterns of the bHLH‐Zip Family Oncoproteins MITF and MYC‐MAX

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