Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1102672 | ENA |
REPOSITORIES: ENA
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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.
2025-01-18 | GSE264536 | GEO
Project description:Sindbis virus structural polyprotein -1 PRF deep mutational scan
| PRJNA720960 | ENA
Project description:DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by involuntary muscle contractions. The disease is caused by mutations in the THAP1 gene, although the exact mechanisms through which these mutations contribute to dystonia's pathophysiology remain elusive. The incomplete penetrance of DYT-tHAP1 dystonia, estimated between 40-60%, indicated that an environmental trigger might be necessary for the disease to manifest in genetically predisposed individuals. To explore the gene-environment interaction in dystonia development, we performed a sciatic nerve crush injury in a genetically predisposed DYTHAP1 heterozygous knockout mouse mode (Thap1+/-). Using a multi-omic approach, we investigated the underlying pathophysiological pathways. Phenotypic analysis with an unbiased deep learning algorithm showed that nerve-injured Thap1+/- mice exhibited more dystonia-like movements over the 12-week experiment than naive Thap1+/- mice. Multi-omic analysis of the cerebellum, striatum, and cortex in nerve-injured Thap1+/- mice revealed altered energy metabolism compared to naive Thap1+/- and nerve-injured wildtype mice. These findings suggest that abnormal energy metabolism in the cerebellum, striatum, and cortex may contribute to the dystonic features observed in nerve-injured Thap1+/- mice.
2025-01-03 | PXD055364 | Pride
Project description:A deep mutational scan of the MHC class I-specific chaperone tapasin
| PRJNA668133 | ENA
Project description:Deep mutational scan of a drug efflux pump reveals its structure-function landscape
| PRJNA782909 | ENA
Project description:Goal of the experiment : Retroviral-mediated gene transfer of the THAP-zinc finger protein THAP1 inhibits endothelial cell proliferation through coordinated repression of critical cell cycle regulators and pRB-E2F target genes. Experimental design: To gain insight into the effects of THAP1 on endothelial cell growth regulatory pathways, we identified THAP1 target genes in primary human endothelial cells using oligonucleotide-based microarray technology. Human umbilical vein endothelial cells (HUVECs) were transduced with pMLV-MCS or pMLV-THAP1 retroviral expression vectors and, after 48h, cells were harvested for isolation of total RNA and preparation of Cy3- or Cy5-labeled cRNA probes, which were hybridized to DNA microarrays that contained 22 000 unique 60-nt oligonucleotide probes representing > 17 000 human genes. Independent microarray experiments were performed after one (#1xTHAP1) or two (#2xTHAP1) consecutive transductions using independent HUVEC primary cell cultures. Dye swap experiments were performed to eliminate the effect of dye bias, and for each gene probe, the data were subjected to statistical analysis to identify those probes for which a significant difference (p value < 0.01) in mean hybridization intensity was observed between HUVECs transduced with pMLV-MCS or pMLV-THAP1 retroviral expression vectors. Among the gene probes demonstrating a significant difference between the two conditions, we selected those whose expression varied in a similar manner in the two independent microarray experiments. . #2xTHAP1 experiment (Microarrays Code Bars 16011521022012 and 16011521022013): comparison of HUVEC-THAP1 and HUVEC-MCS after two consecutive retroviral transductions of HUVECs with pMLV-THAP1 or pMLV-MCS vectors (higher percentage of genes differentially expressed with p value < 0.01; higher folds) #1xTHAP1 experiment (Microarrays Code Bars 16011521025800 and 16011524025685): comparison of HUVEC-THAP1 and HUVEC-MCS after a single retroviral transduction of HUVECs with pMLV-THAP1 or pMLV-MCS vectors (lower percentage of genes differentially expressed with p value < 0.01; lower folds).
2006-09-11 | E-TABM-24 | biostudies-arrayexpress