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Results for “BRD3”

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PubMed2003

[Expression of BRD7-interacting proteins,BRD2 and BRD3, in nasopharyngeal carcinoma tissues].

BACKGROUND & OBJECTIVE: BRD7 is a novel gene tightly associated with nasopharyngeal carcinoma(NPC) cloned by cDNA representational difference analysis (cDNA RDA). Two proteins,BRD2 and BRD3, including bromodomain and interacting with BRD7 protein had been screened from human fetal brain cDNA library by yeast two-hybrid system. This study was designed to further identify the interactions of BRD2 and BRD3 with BRD7 respectively and to investigate the expression and action pattern of BRD2 and BRD3 in NPC. METHODS: BRD2 and BRD3 genes were respectively co-transformed to yeast Y187 with BRD7 gene, then the yeast cotransformers were blotted to nylon membrane. And then the expression of report gene Lac Z by beta-Gal was determined and the interactions of BRD2 and BRD3 proteins with BRD7 protein were identified. Besides,reverse transcription-polymerase chain reaction (RT- PCR) was used to examine the expression of BRD2 and BRD3 genes in normal nasopharyngeal epithelium and NPC biopsies, and to detect the effect of re-expression of BRD7 gene on the expression of BRD2 and BRD3 genes in HNE1 stably transfected BRD7 gene. RESULTS: The yeast transformers showed all blue by yeast two-hybrid system, which further identified that BRD2 and BRD3 proteins could respectively interact with BRD7 protein. Down-expression or loss of BRD2 and BRD3 genes were detectable in NPC biopsies. The expression levels of BRD2 and BRD3 were increasing with the re-expression of BRD7 gene in HNE1 stably transfected with BRD7. CONCLUSION: BRD7 protein could respectively interact with proteins, BRD2 and BRD3, and BRD7 could up-regulate the expression levels of BRD2 and BRD3 genes in mRNA level to some extent. Each of these three homolog proteins might be capable of forming heteromers with the others, which play important roles in the suppression of growth of NPC cells.

Chromosomal Proteins, Non-Histone↗

PubMed2025

BET family BRD3 initiates DSB-induced chromatin remodeling with TIP60 to promote R-loop-mediated HR.

Mechanisms for genome stability in actively transcribed regions are essential for cellular homeostasis; however, these mechanisms are poorly understood. Herein, we identify the bromodomain and extraterminal domain (BET) family BRD3 as the genome caretaker in actively transcribed chromatin. We identify the protein network between BRD3 and chromatin remodeler TIP60. During transcription, BRD3 localizes to actively transcribed chromatin through its N-terminal bromodomains. Following DNA double-strand breaks (DSBs) at the actively transcribed chromatin, the C-terminal extraterminal (ET) domain of BRD3 recruits CHD4 via its KIKL-like motifs to replace HP1 with the TIP60 (Tat-interactive protein, 60 kDa) complex, promoting H4K16 acetylation and MBTD1 recruitment, which creates chromatin barriers to 53BP1. This process recruits BRCA1 and R-loop-processing factors to promote R-loop-mediated homologous recombination (HR) and suppress 53BP1 and mutagenic non-homologous end-joining. Our study elucidates the mechanism by which BRD3 initiates DSB-induced chromatin remodeling by CHD4 and TIP60 to promote R-loop-mediated HR on actively transcribed chromatin to maintain genome stability.

Humans↗

PubMed2004

Identification of unique, differentiation stage-specific patterns of expression of the bromodomain-containing genes Brd2, Brd3, Brd4, and Brdt in the mouse testis.

The bromodomain, an evolutionarily conserved motif that binds acetyl-lysine on histones, is found in many chromatin-associated proteins, transcription factors, and in nearly all known histone acetyltransferases. The BET subclass of bromodomain-containing proteins contains two bromodomains and one ET domain and consists of at least four members in mouse and human, Brd2, Brd3, Brd4, and Brdt. We isolated mouse cDNAs for these genes and studied their expression patterns with particular focus on the testis. Northern hybridization revealed that Brd3 is most abundant in testis, ovary, placenta, uterus, and brain; that Brd4 is rather ubiquitously expressed but is most abundant in mid-gestation embryo, testis, ovary, and brain; and that Brdt is specifically expressed in testis. In situ hybridization and immunostaining on histological sections of mouse testes revealed a strikingly specific and dynamic change of cellular specificity in the germ line during the progression of spermatogenesis. Brd4 is expressed in spermatogonia, Brdt is only expressed in mid- to late-spermatocytes, Brd2 is expressed in diplotene spermatocytes and round spermatids and at low levels in spermatogonia, and Brd3 is expressed in round spermatids. This unique expression pattern suggests that genes in this subclass are not simply redundant. Rather, their expression is tightly regulated in the male germ cell lineage, suggesting that they likely have specific roles in different developmental stages and/or cell types.

Animals↗

PubMed2004

Pre-sertoli specific gene expression profiling reveals differential expression of Ppt1 and Brd3 genes within the mouse genital ridge at the time of sex determination.

In mammals, testis determination is initiated when the SRY gene is expressed in pre-Sertoli cells of the undifferentiated genital ridge. SRY directs the differentiation of these cells into Sertoli cells and initiates the testis differentiation pathway via currently ill-defined mechanisms. Because Sertoli cells are the first somatic cells to differentiate within the developing testis, it is likely that the signals for orchestrating testis determination are expressed within pre-Sertoli cells. We have previously generated a transgenic mouse line that expresses green fluorescent protein under the control of the pig SRY promoter, thus marking pre-Sertoli cells via fluorescence. We have now used suppression-subtractive hybridization (SSH) to construct a normalized cDNA library derived from fluorescence-activated cell sorting (FACS) purified pre-Sertoli cells taken from 12.0 to 12.5 days postcoitum (dpc) fetal transgenic mouse testes. A total of 35 candidate cDNAs for known genes were identified. Detection of Sf1, a gene known for its role in sex determination as well as Vanin-1, Vcp1, Sparc, and Aldh3a1, four genes previously identified in differential screens as gene overexpressed in developing testis compared with ovary, support the biological validity of our experimental model. Whole-mount in situ hybridization was performed on the 35 candidate genes for qualitative differential expression between male and female genital ridges; six were upregulated in the testis and one was upregulated in the ovary. The expression pattern of two genes, Ppt1 and Brd3, were examined in further detail. We conclude that combining transgenically marked fluorescent cell populations with differential expression screening is useful for cell expression profiling in developmental systems such as sex determination and differentiation.

Animals↗

PubMed2005

Differentially expressed genes in endothelial differentiation.

By screening differentially expressed genes in mouse embryonic stem (ES) cells by subtractive hybridization, we identified three conserved but uncharacterized genes encoding bromodomain containing 3 (BRD3), protein lysine methyltransferase (PLM), and kelch domain containing 2 (KLHDC2), which were downregulated during endothelial differentiation. An RNA blot study showed that these genes were markedly expressed in undifferentiated ES cells, whereas the expression was reduced upon endothelial differentiation; a study of mouse endothelium showed a significant reduction in the expression of BRD3. A study of human BRD3, located on chromosome 9 at q34, a region susceptible to genomic rearrangement, showed an altered expression in 4 of 12 patients with bladder cancer, compared with adjacent noncancerous tissues. Taken together with the result of siRNA inhibition showing the positive regulation of cell proliferation by BRD3, it is suggested that this molecule plays a role in allowing cells to enter the proliferative phase of the angiogenic process.

Animals↗

PubMed2006

Bromodomain testis-specific protein is expressed in mouse oocyte and evolves faster than its ubiquitously expressed paralogs BRD2, -3, and -4.

By using in silico methods in a previous study, we identified 100 oocyte-specific genes and 150 genes, enriched in the mouse oocyte. Interestingly, approximately half of the oocyte-specific genes tend to cluster on mouse chromosomes as if they have recently duplicated during evolution. In this study, we focused our attention on mouse BRDT, which belongs to a family of four structurally related proteins characterized by two N-terminal bromodomains and one C-terminal extraterminal domain (ET domain), defining the BET family. In mammals, BRD2, -3, and -4 are ubiquitously expressed, whereas BRDT expression was shown to be restricted to the testis. We were interested to know whether there was a correlation between the evolutionary rate and the specificity of expression of these four paralogous genes. First, we show by RT-PCR and in situ hybridization that BRDT is also expressed in mouse oocyte. Moreover, phylogenetic analyses show that the BRDT germ cell-specific orthology group clearly evolves faster than its ubiquitously expressed paralogs BRD2, BRD3, and BRD4. This suggests that there is a relationship between the evolution of these four groups of orthology and their tissue specificity of expression.

Amino Acid Sequence↗

PubMed2026

Integrative Proteomics and Ubiquitomics Reveal on-Targets and off-Targets of PROTAC dBET1.

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that induce selective degradation of target proteins by hijacking the ubiquitin-proteasome system (UPS). Despite their transformative potential in eliminating disease-associated proteins, comprehensively identifying off-target degradation events remains technically challenging. Here, we employed an integrated proteomic and ubiquitinomic strategy to systematically profile the degradation landscape of the PROTAC molecule dBET1 in Jurkat T cells. By capturing the upstream ubiquitination events─which serve as earlier and more sensitive indicators than total protein abundance─our approach enabled the identification of previously overlooked off-target candidates. While dBET1 efficiently degraded its canonical BET family targets, our data also revealed the mitochondrial outer membrane protein VDAC1 as a putative off-target, evidenced by its depletion and increased multisite ubiquitination. Notably, our analysis framework enabled site-specific resolution of degradation events within BRD3, revealing preferential ubiquitination at functionally essential bromodomains, suggesting that degron-enriched regions may underlie domain-selective degradation. Additionally, dBET1 treatment was associated with mitochondrial depolarization and calcium homeostasis disruption, defects that we hypothesize may be functionally linked to the observed VDAC1 depletion. Together, this study demonstrates that integrating ubiquitomics provides a superior sensitivity layer for PROTAC safety assessment, capable of uncovering mechanism-based liabilities that escape conventional global proteomic screening.

Humans↗