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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics [Hybrid capture]

ABSTRACT: Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics [Hybrid capture]

PROVIDER: PRJNA814331 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18284734.fastq.gz	Fastqsanger.gz
	SRR18284735.fastq.gz	Fastqsanger.gz
	SRR18284736.fastq.gz	Fastqsanger.gz
	SRR18284737.fastq.gz	Fastqsanger.gz
	SRR18284738.fastq.gz	Fastqsanger.gz

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics

Project description:Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders [Saturating mutagenesis]

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics [Hybrid capture]

Project description:Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined "functional hotspots". Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here, we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. A Hybrid capture assay reveals resistance-conferring mutations after degrader treatment. 29 putative target genes were selected to be sequenced. Target gene enrichment from gDNA of treated cells was performed, followed by amplification and sequencing to identify mutations.

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders [Saturating mutagenesis]

Project description:Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders [Saturating mutagenesis]

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders via chemical genetics

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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.

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Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders.

Project description:Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined 'functional hotspots'. Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.

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