Depletion of BRD9-mediated R-loop accumulation inhibits leukemia cell growth via transcription-replication conflict
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1281562 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Bromodomain-containing protein 9 (BRD9) has emerged as a promising therapeutic target for blood cancers, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). PROTAC-based BRD9 degraders effectively hamper the growth and survival of leukemia cells; however, the underlying mechanism of these BRD9 degraders remains unclear. In this study, we demonstrated that depletion of BRD9 triggers DNA damage via R-loop accumulation, leading to conflicts between transcription and replication processes. Replication stress inhibits the proliferation of leukemia cells and promotes their differentiation. Mechanistically, BRD9 plays a pivotal role in recruiting BRD2 and BRD4 to chromatin through direct interactions, which is critical for preventing R-loop formation during transcription. Depletion of BRD9 in leukemia cells reduces the occupancy of BRD2 and BRD4 at R-loop-prone sites, thus promoting R-loop accumulation, transcription-replication collision, excessive DNA damage, and ultimately, the demise of cancer cells. These findings provide valuable insights into the mechanisms by which BRD9 degraders function as effective therapies for leukemia mediated by the pathological accumulation of R-loops.
2025-07-16 | GSE300622 | GEO
Project description:ZFP281-BRCA2 prevents R-loop accumulation during DNA replication
| PRJNA524627 | ENA
Project description:While RNA viruses evade host immune responses by perturbing transcriptional and translational machinery, the host organism counteracts viral invasion through activation of regulated cell death pathways. However, the precise molecular mechanisms underlying host-initiated cell death activation in response to viral infection remain poorly characterized. By genome-wide screening, we identified ribosomal protein RPSA as a broad inducer of RNA virus replication-dependent cell death that confers antiviral protection. Rpsa conditional knockout mice exhibited heightened susceptibility to RNA viruses with attenuated cell death activation in infected tissues. Mechanistically, RNA virus infection triggers K29-linked polyubiquitination of RPSA, which strengthens its binding to the helicase domain of NAT10 and potently inhibits NAT10's helicase activity, thereby blocking R-loop resolution. The resulting R-loop accumulation drives DNA damage-mediated cell death execution. Our findings uncover a novel intranuclear "inside-out" R-loop-driven cell death pathway orchestrated by RPSA, providing fresh insights into virus-host interactions and identifying potential therapeutic targets for RNA viral infections.
2025-07-18 | GSE300291 | GEO
Project description:R-loops are prevalent in mammalian genomes and involved in many fundamental cellular processes. Depletion of BRCA2 leads to aberrant R-loop accumulation, contributing to genome instability. Here, we show that ZFP281 cooperates with BRCA2 in preventing R-loop accumulation to facilitate DNA replication in embryonic stem cells. Mechanistically, we demonstrate that ZFP281 can interact with BRCA2, and that BRCA2 is enriched at G/C-rich promoters and requires both ZFP281 and PRC2 for its proper recruitment to the bivalent chromatin at the genome-wide scale. Furthermore, depletion of ZFP281 or BRCA2 leads to accumulation of R-loops over the bivalent regions, and compromises activation of the developmental genes by retinoic acid during stem cell differentiation. In summary, our results reveal that ZFP281 recruits BRCA2 to the bivalent chromatin regions to ensure proper progression of DNA replication through preventing persistent R-loops.
2022-05-31 | GSE127262 | GEO
Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+ cells. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOCS3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.
2019-05-02 | GSE129437 | GEO
Project description:While RNA viruses evade host immune responses by perturbing transcriptional and translational machinery, the host organism counteracts viral invasion through activation of regulated cell death pathways. However, the precise molecular mechanisms underlying host-initiated cell death activation in response to viral infection remain poorly characterized. By genome-wide screening, we identified ribosomal protein RPSA as a broad inducer of RNA virus replication-dependent cell death that confers antiviral protection. Rpsa conditional knockout mice exhibited heightened susceptibility to RNA viruses with attenuated cell death activation in infected tissues. Mechanistically, RNA virus infection triggers K29-linked polyubiquitination of RPSA, which strengthens its binding to the helicase domain of NAT10 and potently inhibits NAT10's helicase activity, thereby blocking R-loop resolution. The resulting R-loop accumulation drives DNA damage-mediated cell death execution. Our findings uncover a novel intranuclear "inside-out" R-loop-driven cell death pathway orchestrated by RPSA, providing fresh insights into virus-host interactions and identifying potential therapeutic targets for RNA viral infections.
2025-07-18 | GSE300469 | GEO
Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer stem cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOC3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.
2019-11-11 | PXD013245 | Pride
Project description:Sexual reproduction brings genes from two parents â matrigenes and patrigenes â into one individual. These genes, despite being unrelated, should show nearly perfect cooperation because each gains equally through production of offspring. However, an individualâs matrigenes and patrigenes can have different probabilities of being present in other relatives, so that kin selection could act on them differently. Such intragenomic conflict could be implemented by partial or complete silencing (imprinting) of an allele by one of the parents. Evidence supporting this theory is seen in offspring-mother interactions, with patrigenes favoring acquisition of more of the mother's resources if some of the costs fall on half siblings who do not share the patrigene. The kinship theory of intragenomic conflict is little tested in other contexts, but it predicts that matrigene-patrigene conflict may be rife in social insects. We tested the hypothesis that honey bee worker reproduction is promoted more by patrigenes than matrigenes by comparing across 9 reciprocal crosses of two distinct genetic stocks. As predicted, hybrid workers show reproductive trait characteristics of their paternal stock, indicating enhanced activity of the patrigenes on these traits, greater patrigenic than matrigenic expression, and significantly increased patrigenic biased expression in reproductive workers. These results support both the general prediction that matrigene-patrigene conflict occurs in social insects and the specific prediction that honey bee worker reproduction is driven more by patrigenes. The success of these predictions suggests that intragenomic conflict may occur in many contexts where matrigenes and patrigenes have different relatednesses to affected kin. Testing the kinship theory of intragenomic conflict in honey bees
2015-12-19 | E-GEOD-76164 | biostudies-arrayexpress
Project description:NUSAP1 interactome datasets contain Flag-NUSAP1 AP-MS, identifying ILF2, DHX9, and other RNA binding proteins as novel interactors. These mass spec data and other biochemical data demonstrate NUSAP1 novel roles in binding to ILF2 and modulating R-loop accumulation and DNA damage response.
| MSV000090440 | MassIVE
Project description:Arginine methylation is a common posttranslational modification that is catalyzed by a family of protein arginine methyltransferases. Recognition of methylarginine marks by effector proteins (“readers”) is a critical link between arginine methylation and various cellular processes. We recently identified methylation of AKT1 at Arg391 by PRMT5, but the reader for this methylation has yet to be characterized. Here, we show that BRD9, a reader of acetylated lysine, unexpectedly recognizes Arg391-methylated AKT1 through an aromatic cage in its bromodomain. Disrupting the methylarginine reader function of BRD9 suppresses AKT activation and tumorigenesis. RNA-sequencing data shows that BRD9 and AKT co-regulate a hallmark transcriptional program in part through EZH2-mediated H3K27 trimethylation. Lastly, we find that inhibitors of BRD9 and EZH2 display synergistic effects on inhibition of cell viability and tumor growth. Together, our study demonstrates that BRD9 serves as a methylarginine reader to promote AKT-EZH2 oncogenic signaling and combined inhibition of BRD9 and EZH2 is a potential strategy for cancer therapy.
2025-03-18 | PXD058540 | Pride