The genome is organized into large scale structures in the interphase nucleus. Pericentromeric heterochromatin represents one such compartment characterized by histones H3 and H4 tri-methylated at K9 and K20 respectively and with a correspondingly low level of histone acetylation. HP1 proteins are concentrated in pericentric heterochromatin and histone deacetylase inhibitors such as trichostatin A (TSA) promote hyperacetylation of heterochromatic nucleosomes and the dispersal of HP1 proteins. We observed that in mouse cells, which contain prominent heterochromatin, DNA topoisomerase IIβ (topoIIβ) is also concentrated in heterochromatic regions. Similarly, a detergent-resistant fraction of topoIIβ is associated with heterochromatin in human cell lines. Treatment with TSA displaced topoIIβ from the heterochromatin with similar kinetics to the displacement of HP1β. Topoisomerase II is the cellular target for a number of clinically important cytotoxic anti-cancer agents known collectively as topoisomerase poisons, and it has been previously reported that histone deacetylase inhibitors can sensitize cells to these drugs. While topoIIα appears to be the major target for most topoisomerase poisons, histone deacetylase-mediated potentiation of these drugs is dependent on topoIIβ. We find that while prior treatment with TSA did not increase the quantity of etoposide-mediated topoIIβ-DNA covalent complexes, it did result in a shift in their distribution from a largely heterochromatin-associated to a pannuclear pattern. We suggest that this redistribution of topoIIβ converts this isoform of topoII to a effective relevant target for topoisomerase poisons.

中文翻译：

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组蛋白去乙酰化酶抑制将拓扑异构酶 IIb 从异染色质重新分配到常染色质

基因组在间期细胞核中被组织成大规模的结构。着丝粒周围异染色质代表了一种这样的隔室，其特征在于组蛋白 H3 和 H4 分别在 K9 和 K20 三甲基化，并具有相应低水平的组蛋白乙酰化。HP1 蛋白集中在中心异染色质中，组蛋白去乙酰化酶抑制剂如曲古抑菌素 A (TSA) 促进异染色质核小体的高乙酰化和 HP1 蛋白的分散。我们观察到，在含有显着异染色质的小鼠细胞中，DNA 拓扑异构酶 IIβ (topoIIβ) 也集中在异染色质区域。类似地，topoIIβ 的去污剂抗性部分与人类细胞系中的异染色质相关。用 TSA 处理从异染色质中置换出 topoIIβ，其动力学与置换 HP1β 相似。拓扑异构酶 II 是许多临床上重要的细胞毒性抗癌剂（统称为拓扑异构酶毒物）的细胞靶点，此前曾报道组蛋白脱乙酰酶抑制剂可使细胞对这些药物敏感。虽然 topoIIα 似乎是大多数拓扑异构酶毒物的主要靶标，但组蛋白脱乙酰酶介导的这些药物的增强作用依赖于 topoIIβ。我们发现，虽然先前用 TSA 治疗并没有增加依托泊苷介导的 topoIIβ-DNA 共价复合物的数量，但它确实导致它们的分布从主要的异染色质相关转变为泛核模式。