Transcriptome analysis for modulating ubiquitin siganlling in the amniote embryo via phosphoregulation of the E2 enzyme UBE2D3
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA485078 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7659050_1.fastq.gz | Fastqsanger.gz | |||
| SRR7659050_2.fastq.gz | Fastqsanger.gz | |||
| SRR7659051_1.fastq.gz | Fastqsanger.gz | |||
| SRR7659051_2.fastq.gz | Fastqsanger.gz | |||
| SRR7659052_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Understanding the transcriptional effects of a gain of function mutation of the E2 enzyme UBE2D3 in embryonic stem cells Methods: mRNA profiles of wt E14 ES cells and UBE2D3 Ser138Ala mutant ES cells were generated
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Project description:UBE2J1 is the E2 Ubiquitin Conjugating Enzyme Required for Androgen Receptor Degradation
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Project description:The Androgen Receptor (AR) is a pivotal protein in human physiology, exerting significant influence on both male and female physiology (PMID: 18434134, 25905231). Functioning as a nuclear transcription factor, AR binds to testosterone, translocates to the nucleus, and subsequently regulates the expression of numerous genes, impacting vital cellular processes such as cell proliferation, differentiation, and apoptosis (PMID: 4810760, 25237629). The prominent role of AR in human physiology is particularly notable in the context of prostate cancer initiation, where aberrant AR signaling has been identified as a key driver in tumorigenesis (PMID: 4810760, 27057074, 37429011). However, despite the considerable success of the current anti-androgen therapeutic approach, it faces the formidable challenge of drug resistance, significantly limiting the clinical outcome for patients and necessitating the urgent development of new therapeutic approaches to overcome resistance (PMID: 26563462, 24881730, 31363002, 35582713). Notably, one key feature of antiandrogen resistance is the sustained or enhanced AR signaling observed in many resistant tumors (PMID: 26563462, 34449248, 23580326), although the underlying molecular mechanisms remain largely unclear. Protein degradation, with ubiquitination at its core, plays a critical role in cell functionality, ensuring the elimination of redundant and harmful proteins (PMID: 16738015, 33634825). This intricate process involves the attachment of small proteins called ubiquitin to target proteins, marking them for degradation. Dysregulation of ubiquitination can lead to the accumulation of oncogenic proteins, contributing to tumorigenesis and therapy resistance in various cancers (PMID: 32296023, 33004065). The degradation of proteins is a complex process that involves the coordination of E1, E2 and E3 enzymes, with E3 enzymes binding to the target protein (PMID: 21111229, 20930542). Logically, research has focused on finding E3s targeting AR for degradation but has overlooked the role that E2s play in the ubiquitination process. In recent years, E2s have been shown to dictate the how and where ubiquitin gets attached in the target protein, dictating the fate of the protein (PMID: 27002219, 19851334). Therefore, finding the E2 involved in the degradation of AR can prove to be essential. In this study, we conducted an in vivo library screening approach and identified UBE2J1 as the bona fide E2 ubiquitin conjugating enzyme for AR ubiquitination. Our results demonstrated that the frequent loss of UBE2J1 in prostate cancer leads to dysregulated and impaired AR ubiquitination and degradation. Consequently, this promotes the accumulation of AR proteins and confers resistance to antiandrogen treatment in UBE2J1-deficient prostate cancer cells. To address this, we developed an innovative ubiquitination-based AR degrader that effectively restores AR ubiquitination, thereby resensitizing prostate cancer cells to antiandrogen therapy. These findings not only unveil the pivotal role of UBE2J1 as the crucial E2 ubiquitin conjugating enzyme for AR degradation but also shed light on a novel mechanism through which advanced prostate cancer cells upregulate AR protein levels, thereby acquiring resistance to existing antiandrogen therapy. These novel insights hold the potential to inform the development of more effective therapeutic strategies against advanced prostate cancers.
2024-02-09 | GSE240305 | GEO
Project description:The H3K27M oncogenic histone (oncohistone) mutation drives ~80% of incurable childhood brain tumors known as diffuse midline gliomas (DMGs). The major molecular feature of H3K27M mutant DMGs is a global loss of H3K27 tri-methylation (H3K27me3), a phenotype conserved in Caenorhabditis elegans (C. elegans). Here we perform unbiased genome-wide suppressor screens in C. elegans expressing H3K27M, and isolate 20 suppressors, all of which at least partially restore H3K27me3. 19/20 suppressor mutations map to the same histone H3.3 gene in which the K27M mutation was originally introduced. Most of these create single amino acid substitutions between residues R26-Y54, which do not disrupt oncohistone expression. Rather, they are predicted to impair interactions with the Polycomb Repressive Complex 2 (PRC2) and are functionally conserved in human cells. Further, we mapped a single extragenic H3K27M suppressor to ubc-20, an E2 ubiquitin conjugating enzyme, whose loss rescued H3K27me3 to nearly 50% wild-type levels despite continued oncohistone expression and chromatin incorporation. We demonstrate that ubc-20 is the major enzyme responsible for generating di-ubiquitinated histone H2B. Our study provides in vivo support for existing models of PRC2 inhibition via direct oncohistone contact, and suggests that the effects of H3K27M may be modulated by H2B ubiquitination.
2024-11-20 | GSE275118 | GEO
Project description:Genetic variation in the enzymes that catalyze posttranslational modification of proteins is a potentially important source of phenotypic variation during evolution. Ubiquitination is one such modification that affects turnover of virtually all of the proteins in the cell in addition to roles in signaling and epigenetic regulation. UBE2D3 is a promiscuous E2 enzyme, which acts as an ubiquitin donor for E3 ligases that catalyze ubiquitination of developmentally important proteins. We have used protein sequence comparison of UBE2D3 orthologs to identify a position in the C-terminal α-helical region of UBE2D3 that is occupied by a conserved serine in amniotes and by alanine in anamniote vertebrate and invertebrate lineages. Acquisition of the serine (S138) in the common ancestor to modern amniotes created a phosphorylation site for Aurora B. Phosphorylation of S138 disrupts the structure of UBE2D3 and reduces the level of the protein in mouse embryonic stem cells (ESCs). Substitution of S138 with the anamniote alanine (S138A) increases the level of UBE2D3 in ESCs as well as being a gain of function early embryonic lethal mutation in mice. When mutant S138A ESCs were differentiated into extraembryonic primitive endoderm, levels of the PDGFRα and FGFR1 receptor tyrosine kinases were reduced and primitive endoderm differentiation was compromised. Proximity ligation analysis showed increased interaction between UBE2D3 and the E3 ligase CBL and between CBL and the receptor tyrosine kinases. Our results identify a sequence change that altered the ubiquitination landscape at the base of the amniote lineage with potential effects on amniote biology and evolution.
| S-EPMC7306689 | biostudies-literature
Project description:The cyclic oligonucleotide-based anti-phage signalling system (CBASS) is a typeof innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS utilizes cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homolog of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, we report that a bacterial E2 enzyme regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C-terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond, and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.
2024-02-27 | PXD050178 |
Project description:We identified a novel E2 ubiquitin conjugating activity within the C-terminus domain of MUC1. To determine if E2 ubiquitin conjugating activity of MUC1 is responsible for regulating expression of oncogenic genes we isolated RNA from vector control cells, MUC1 wildtype overexpression cells, and cells that express a serine mutant lacking E2 activity.
2016-08-01 | GSE60339 | GEO
Project description:We identified a novel E2 ubiquitin conjugating activity within the C-terminus domain of MUC1. To determine if E2 ubiquitin conjugating activity of MUC1 is responsible for regulating expression of oncogenic genes we isolated RNA from vector control cells, MUC1 wildtype overexpression cells, and cells that express a serine mutant lacking E2 activity. RNA was isolated from each of the 3 cell lines, S2013.Neo, S2013.MUC1-WT, and S2013.MUC1-Ser. Gene expression was analyzed by spotted microarray and the differences in gene expression were calculated between the cell lines
2016-08-01 | E-GEOD-60339 | biostudies-arrayexpress
Project description:The ubiquitin E2 enzyme UBE2E1 is able to catalyse ubiquitination modification of KEGYES/KEGYEE sequence-containing proteins in a manner that does not require an E3 enzyme. Here, we investigate the binding hotspot regions of UBE2E1 with the sequence KEGYES by hydrogen-deuterium exchange mass spectrometry.
2024-02-07 | PXD048115 | Pride
Project description:Neurodegenerative disorders are status in which neuronal cell death, miscommunications between synapse, and abnormal accumulation of proteins in the brain. Alzheimer’s disease (AD) is one of the age-related disorders which is most common degenerative disorders today, and strongly involved memory consolidation and cognitive in the brain. Amyloid-β and tau proteins are trigger for AD pathogenesis, and usually use for AD candidate biomarkers in the clinical research. Especially, clinical exam, brain imaging and molecular biological methods are being used to diagnosis for AD. Genome-wide association study (GWAS) is new biomedical method, and use contribute to understanding of many human diseases included brain diseases. Here, we identified ubiquitin conjugating enzyme E2 (Ube2) gene expression in the neuron through GWAS. The subfamilies of Ube2 genetic expression and inborn errors affect ubiquitin proteasome system (UPS) leading to protein degradation in the brain. We found that only Ube2h mRNA transcription was significantly increased in the blood from AD, however we did not find change of Ube2 subfamily genes expression in the blood and brain tissue. These data may provide information of diagnosis or clinical approach, and suggest that cell-free circulating Ube2h mRNA is novel potential biomarker for AD.
2020-12-31 | GSE147792 | GEO