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MYC modulates TOP2A diffusion to promote substrate detection and activity [CAD-seq]

ABSTRACT: Topoisomerases are essential enzymes that alleviate DNA supercoiling by cleaving and resealing DNA strands. Regulation of their abundance and activity is crucial for maintaining genomic stability and supporting nuclear functions. Previously, we showed that the oncoprotein MYC recruits and stimulates topoisomerases to remove DNA entanglements generated by oncogenic transcription. Understanding this mechanism may suggest methods to inhibit MYC-driven topoisomerase activation, thereby selectively targeting tumor-specific transcription. Here, we demonstrate that the essential topoisomerase TOP2A in human cells exists in a dynamic equilibrium between sequestration in the nucleolus, substrate searching in transcription hubs, and active engagement on chromatin. This equilibrium is highly responsive to changes in DNA topology, allowing cells to regulate TOP2A levels in the nucleoplasm. Using single molecule tracking, we show that MYC accelerates TOP2A diffusion in cells. In vitro, we demonstrate that MYC decreases the size of TOP2A condensates, likely by limiting non-specific self interactions. By increasing TOP2A diffusion, MYC promotes substrate binding and increases TOP2A engagement on the chromatin genome-wide, revealing the mechanism underlying MYC stimulation of TOP2A activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298118 | GEO | 2026/01/26

REPOSITORIES: GEO

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MYC modulates TOP2A diffusion to promote substrate detection and activity [SLAM-seq]

Project description:Topoisomerases are essential enzymes that alleviate DNA supercoiling by cleaving and resealing DNA strands. Regulation of their abundance and activity is crucial for maintaining genomic stability and supporting nuclear functions. Previously, we showed that the oncoprotein MYC recruits and stimulates topoisomerases to remove DNA entanglements generated by oncogenic transcription. Understanding this mechanism may suggest methods to inhibit MYC-driven topoisomerase activation, thereby selectively targeting tumor-specific transcription. Here, we demonstrate that the essential topoisomerase TOP2A in human cells exists in a dynamic equilibrium between sequestration in the nucleolus, substrate searching in transcription hubs, and active engagement on chromatin. This equilibrium is highly responsive to changes in DNA topology, allowing cells to regulate TOP2A levels in the nucleoplasm. Using single molecule tracking, we show that MYC accelerates TOP2A diffusion in cells. In vitro, we demonstrate that MYC decreases the size of TOP2A condensates, likely by limiting non-specific self interactions. By increasing TOP2A diffusion, MYC promotes substrate binding and increases TOP2A engagement on the chromatin genome-wide, revealing the mechanism underlying MYC stimulation of TOP2A activity.

2026-01-26 | GSE311617 | GEO

Topoisomerase IIA in Adult NSCs Regulates SVZ Neurogenesis by Transcriptional Activation of Usp37 (ChIP-Seq)

Project description:Topoisomerase IIA (TOP2a) has been traditionally known as an important nuclear enzyme that resolves entanglements and relieves torsional stress of DNA double strands. However, little is known about its function in genomic transcriptional regulation, especially during adult neurogenesis. Here, we show that TOP2a is preferentially expressed in neurogenic niches in the brain of adult mice, such as the subventricular zone (SVZ). Conditional knockout of Top2a in adult neural stem cells (NSCs) in the SVZ significantly inhibits their self-renewal and proliferation and ultimately reduces neurogenesis. To gain insight into the molecular mechanisms by which TOP2a regulates adult NSCs, we perform RNA-sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) and identify ubiquitin-specific proteases 37 (Usp37) as a direct TOP2a target gene. Importantly, overexpression of Usp37 is sufficient to rescue the impaired self-renewal ability of adult NSCs caused by Top2a knockdown. Taken together, our proof-of-principle study illustrates a TOP2a/Usp37-mediated novel molecular mechanism of adult neurogenesis, which will significantly expand our understanding of the function of topoisomerase in adult brain.

2022-09-20 | GSE192397 | GEO

Topoisomerase IIA in Adult NSCs Regulates SVZ Neurogenesis by Transcriptional Activation of Usp37 (RNA-Seq)

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MYC assembles and stimulates topoisomerases 1 & 2 in a “topisome” [cross-CAD-seq]

Project description:High-intensity transcription and replication supercoil DNA to levels that can impede or halt these processes. As a potent transcription amplifier and replication accelerator, the proto-oncogene MYC must somehow manage these high levels of torsional stress. By comparing gene expression with the recruitment of topoisomerases and MYC to promoters, we surmised a direct association of MYC with Topoisomerases 1 (TOP1) and 2A (TOP2A) that was confirmed in vitro and in vivo. Beyond recruiting topoisomerases, MYC directly stimulates their activities in vitro and in vivo. We identify a MYC-nucleated “topoisome” complex that unites and increases the levels of both both TOP1 and TOP2, as well as their activities at promoters and enhancers. Whether TOP2A or TOP2B is included in the topoisome, is dictated by the presence of c-MYC or MYCN, respectively. Thus, in vivo and in vitro, MYC assembles tools that simplify DNA topology and promote genome function under high output conditions.

2021-12-09 | GSE181449 | GEO

MYC assembles and stimulates topoisomerases 1 & 2 in a “topisome” [CAD-seq]

2021-12-09 | GSE181448 | GEO

MYC assembles and stimulates topoisomerases 1 & 2 in a “topisome” [ChIP-seq]

2021-12-09 | GSE181447 | GEO

Genome-wide Mapping of Topoisomerase Binding Sites Suggests Topoisomerase 3a (TOP3A) as a Reader of Transcription-Replication Conflicts (TRC)

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

Topological regulation of the estrogen transcriptional response by ZATT-mediated inhibition of TOP2B activity [ChIP-Seq]

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

Topological regulation of the estrogen transcriptional response by ZATT-mediated inhibition of TOP2B activity [ATAC-Seq]

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Topological regulation of the estrogen transcriptional response by ZATT-mediated inhibition of TOP2B activity [ICE-Seq]

2025-12-31 | GSE236413 | GEO