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Identifying THAP1 target genes in HEK-293T cells

ABSTRACT: Identifying THAP1 target genes in HEK-293T cells

PROVIDER: PRJNA1103109 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28764149_1.fastq.gz	Fastqsanger.gz
	SRR28764149_2.fastq.gz	Fastqsanger.gz
	SRR28764150_1.fastq.gz	Fastqsanger.gz
	SRR28764150_2.fastq.gz	Fastqsanger.gz
	SRR28764151_1.fastq.gz	Fastqsanger.gz

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Identifying THAP1 target genes in HEK-293T cells

Project description:The 26S proteasome is a multi-catalytic protease that serves as the endpoint for protein degradation via the ubiquitin-proteasome system. Proteasome function requires the concerted activity of 33 distinct gene products, but how the expression of proteasome subunits is regulated in mammalian cells remains poorly understood. Leveraging coessentiality data from the DepMap project, here we characterize an essential role for the Dystonia gene THAP1 in maintaining the basal expression of PSMB5. PSMB5 insufficiency resulting from loss of THAP1 leads to defects in proteasome assembly, impaired proteostasis and cell death. The toxicity associated with loss of THAP1 can be rescued upon exogenous expression of PSMB5, explaining the molecular basis for their coessentiality. Leveraging a fluorescent reporter knocked-in to the endogenous PSMB5 locus, we define the transcriptional targets of THAP1 through RNA-seq analysis and perform a deep mutational scan to systematically assess the function of thousands of single amino acid THAP1 variants. Altogether, these data identify THAP1 as a new regulator of proteasome function and suggest that aberrant proteostasis may contribute to the pathogenesis of THAP1 Dystonias.

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