Similar Datasets
Project description:Nalm 6 WT Nalm6 BKO Nalm 6 A hets
| PRJNA623327 | ENA
Project description:The location of TOP2A and TOP2B was determined in MCF7 cells with and without estradiol treatment.
2026-07-01 | GSE337189 | GEO
Project description:Topoisomerase II (TOP2) poisons, such as etoposide and doxorubicin, are potent antineoplastic drugs that are used to treat a variety of solid tumors and leukemias. Yet these drugs also cause significant secondary malignancies and toxicity to postmitotic cells. Proliferating mammalian cells express two TOP2 isoforms, TOP2A and TOP2B, while postmitotic cells only express TOP2B. Selectively targeting TOP2A, but not TOP2B, could thus prevent secondary toxicity in postmitotic cells, but such isoform-selective targeting strategies remain elusive. Here we report that the heat shock transcription factor, HSF1, facilitates the catalytic engagement of TOP2B on chromatin. Purified recombinant HSF1 stimulates the DNA cleavage and relaxation activity of purified TOP2B. Using atomic force microscopy, we show that HSF1 also enhances the recycling of TOP2B for subsequent rounds of DNA relaxation. TOP2B co-occupies the genome with HSF1 in both postmitotic and dividing cells, and either the knockdown or inhibition of HSF1 reduces the levels of catalytically engaged TOP2B. Intriguingly, HSF1 neither significantly interacts with TOP2A nor enhances its catalytic activity. Furthermore, pharmacological HSF1 inhibitors protect postmitotic cells from the cytotoxicity of TOP2 poisons without compromising their ability to kill cancer cells, revealing a potential strategy for minimizing the side-effects of TOP2 poison-based chemotherapy.
2026-07-14 | GSE273874 | GEO
Project description:Anthracyclines are potent chemotherapeutic agents known for their efficacy in treating various cancers via inhibition of topoisomerase II alpha (TOP2A). However, their clinical use is limited due to cardiotoxicity, primarily attributed to off-target inhibition of topoisomerase II beta (TOP2B) in cardiomyocytes. The well-accepted mechanism involves TOP2B inhibition as a key driver of this toxicity. Here, we identify a novel mechanism of anthracycline-induced cardiotoxicity (AIC) involving upregulated TOP2B expression and its direct impact on cardiomyocyte function. Our data show that doxorubicin significantly increased TOP2B protein levels in cardiomyocytes in AIC mouse model. The cardiomyocyte-specific, tamoxifen-inducible TOP2B transgenic mice exhibited pathophysiological features consistent with doxorubicin-induced cardiotoxicity, even without exposure to anthracyclines. Additionally, we discovered that TOP2B binds to SMYD1, a histone methyltransferase critical for muscle cell function. Mutations in SMYD1 are known to cause cardiomyopathy and heart failure in humans, and loss of Smyd1 in mice results in a phenotype resembling AIC. More importantly, TOP2B ASO pretreatment can succussfully prevent the AIC in TOP2B transgenic mice and AIC mouse models. Our findings reveal a novel role for TOP2B in AIC, demonstrating that its upregulation disrupts SMYD1 function in cardiomyocytes, contributing to cardiotoxicity. This study also highlights the therapeutic potential of targeting TOP2B using ASO for preventing AIC in cancer patients, offering new insights into cardioprotective strategies
2026-05-05 | PXD077277 | Pride
Project description:Vaccinia virus is a large enveloped DNA virus, which, like all poxviruses, replicates in the cytoplasm of infected cells. Vaccinia was historically thought to encode all the proteins required for its replication. However, recent findings have shown that nuclear host proteins are redirected to the cytoplasm to facilitate viral replication. Among these, topoisomerase 2α (TOP2A) and 2β (TOP2B), which mediate nuclear transcription, DNA replication, and chromosome segregation are the most abundant host proteins associated with nascent viral genomes. Here, we investigate the mechanisms driving TOP2A and TOP2B cytoplasmic translocation and their role in viral replication. We found that early viral protein synthesis induces the cytosolic relocalization of both isoforms, which are subsequently recruited to viral factories by an interaction of their C-terminal domains with the viral ligase, A50. TOP2A promotes replication by interacting with the vaccinia DNA replication machinery. In contrast, TOP2B suppresses replication by enhancing the formation of double-stranded RNA and antiviral granules, containing components of the tRNA splicing ligase complex. Our analysis provides new insights into host-pathogen interactions during poxvirus infection and the role of topoisomerase 2 outside of the nucleus.
2025-06-30 | PXD060689 | Pride
Project description:Human type-II topoisomerases, TOP2A and TOP2B, remove DNA supercoiling associated with transcription, have been shown to affect several gene-expression programs, and have been correlatively linked to 3D genome architecture, although through a still poorly understood function. To study in depth the regulatory roles of TOP2 paralogs, we have used the well-characterized cellular response to estrogen as a model of acute transcriptional induction involving a rewiring of genome organization. We find that, as expected for a topoisomerase, TOP2A facilitates transcription. TOP2B, however, limits the expression of estrogen responsive genes under basal non-induced conditions, while, in response to estrogen treatment, its activity is locally downregulated to allow an accumulation of DNA supercoiling, and to favor the necessary regulatory chromatin contacts. Furthermore, this estrogen-mediated inhibition of TOP2B function requires estrogen receptor α (ERα), a non-catalytic function of TOP2A, and the action of the atypical SUMO-ligase ZATT. This mechanism of topological transcriptional-control may be shared by additional gene-expression circuits, in particular those involving a rewiring of genome organization, and highlights the relevance of DNA supercoiling and topoisomerases as central actors of genome dynamics.
2025-12-31 | GSE236413 | GEO
Project description:Human type-II topoisomerases, TOP2A and TOP2B, remove DNA supercoiling associated with transcription, have been shown to affect several gene-expression programs, and have been correlatively linked to 3D genome architecture, although through a still poorly understood function. To study in depth the regulatory roles of TOP2 paralogs, we have used the well-characterized cellular response to estrogen as a model of acute transcriptional induction involving a rewiring of genome organization. We find that, as expected for a topoisomerase, TOP2A facilitates transcription. TOP2B, however, limits the expression of estrogen responsive genes under basal non-induced conditions, while, in response to estrogen treatment, its activity is locally downregulated to allow an accumulation of DNA supercoiling, and to favor the necessary regulatory chromatin contacts. Furthermore, this estrogen-mediated inhibition of TOP2B function requires estrogen receptor α (ERα), a non-catalytic function of TOP2A, and the action of the atypical SUMO-ligase ZATT. This mechanism of topological transcriptional-control may be shared by additional gene-expression circuits, in particular those involving a rewiring of genome organization, and highlights the relevance of DNA supercoiling and topoisomerases as central actors of genome dynamics.
2025-12-31 | GSE236412 | GEO
Project description:Human type-II topoisomerases, TOP2A and TOP2B, remove DNA supercoiling associated with transcription, have been shown to affect several gene-expression programs, and have been correlatively linked to 3D genome architecture, although through a still poorly understood function. To study in depth the regulatory roles of TOP2 paralogs, we have used the well-characterized cellular response to estrogen as a model of acute transcriptional induction involving a rewiring of genome organization. We find that, as expected for a topoisomerase, TOP2A facilitates transcription. TOP2B, however, limits the expression of estrogen responsive genes under basal non-induced conditions, while, in response to estrogen treatment, its activity is locally downregulated to allow an accumulation of DNA supercoiling, and to favor the necessary regulatory chromatin contacts. Furthermore, this estrogen-mediated inhibition of TOP2B function requires estrogen receptor α (ERα), a non-catalytic function of TOP2A, and the action of the atypical SUMO-ligase ZATT. This mechanism of topological transcriptional-control may be shared by additional gene-expression circuits, in particular those involving a rewiring of genome organization, and highlights the relevance of DNA supercoiling and topoisomerases as central actors of genome dynamics.
2025-12-31 | GSE236411 | GEO
Project description:TOP2A and TOP2B bind and cleave genomic DNA. These enzymes are targeted by some anti-cancer drugs that stabilise the enzyme complexes on the DNA. Whole genome TOP2 ChIP-seq was carried out on human KG-1 cells in the presence and absence of the topoisomerase targeting drugs Etoposide and Mitoxantrone in the absence of formaldehyde.
2025-07-24 | GSE280809 | GEO
Project description:Both transcription and replication can take place simultaneously on the same DNA template, potentially leading to transcription-replication conflicts (TRCs) and topological problems. Here we asked which topoisomerase(s) is/are the best candidate(s) for sensing TRC. Genome-wide topoisomerase binding sites were mapped in parallel for all the nuclear topoisomerases (TOP1, TOP2A, TOP2B, TOP3A and TOP3B). To increase the signal to noise ratio (SNR), we used ectopic expression of those topoisomerases in H293 cells followed by a modified CUT&Tag method. Although each topoisomerase showed distinct binding patterns, all topoisomerase binding signals positively correlated with gene transcription. TOP3A binding signals were suppressed by DNA replication inhibition. This was also observed but to a lesser extent for TOP2A and TOP2B. Hence, we propose the involvement of TOP3A in sensing both head-on TRCs (HO-TRCs) and codirectional TRCs (CD-TRCs). In which case, the TOP3A signals appear concentrated within the promoters and first 20 kb regions of the 5’ -end of genes, suggesting the prevalence of TRCs and the recruitment of TOP3A in the 5’-regions of transcribed and replicated genes.
2024-07-31 | GSE269841 | GEO