Histone deacetylase inhibition redistributes topoisomerase IIβ from heterochromatin to euchromatin
Histone deacetylase inhibition redistributes topoisomerase IIβ from heterochromatin to euchromatin
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DOI：
10.4161/nucl.2.1.14194
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发表时间：
2011-01-01
期刊：
影响因子：
3.7
通讯作者：
Austin, Caroline A.
中科院分区：
文献类型：
--
作者：
Cowell, Ian G.;Papageorgiou, Nikolaos;Austin, Caroline A.
基因组在间期细胞核中被组织成大规模的结构。周中心点异染色质代表这样一个室室，其特征是组蛋白H3和H4分别在K9和K20位点三甲基化，组蛋白乙酰化水平相应较低。HP1蛋白集中在中心周围异染色质中，组蛋白去乙酰化酶抑制剂如trichostatin A （TSA）促进异染色质核小体的超乙酰化和HP1蛋白的分散。我们观察到，在含有显著异染色质的小鼠细胞中，DNA拓扑异构酶II β (topoII β)也集中在异染色质区域。类似地，topoII β抗洗涤剂部分与人类细胞系中的异染色质有关。TSA处理将topoII β从异染色质中置换，其动力学与HP1 β的置换相似。拓扑异构酶II是许多临床上重要的细胞毒性抗癌药物的细胞靶点，这些药物统称为拓扑异构酶毒药，以前有报道称组蛋白去乙酰化酶抑制剂可以使细胞对这些药物敏感。虽然topoII α似乎是大多数拓扑异构酶毒药的主要靶点，但组蛋白去乙酰酶介导的这些药物的增强依赖于topoII β。我们发现，虽然先前的TSA治疗并没有增加依托泊苷介导的topoII β - dna共价复合物的数量，但它确实导致了它们的分布从主要的异染色质相关到泛核模式的转变。我们认为这种topoII β的再分配将topoII的这种同工异构体转化为拓扑异构酶毒素的有效相关靶标。
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 II beta (topoII beta) is also concentrated in heterochromatic regions. Similarly, a detergent-resistant fraction of topoII beta is associated with heterochromatin in human cell lines. Treatment with TSA displaced topoII beta from the heterochromatin with similar kinetics to the displacement of HP1 beta. 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 topoII alpha appears to be the major target for most topoisomerase poisons, histone deacetylase-mediated potentiation of these drugs is dependent on topoII beta. We find that while prior treatment with TSA did not increase the quantity of etoposide-mediated topoII beta-DNA covalent complexes, it did result in a shift in their distribution from a largely heterochromatin-associated to a pan-nuclear pattern. We suggest that this redistribution of topoII beta converts this isoform of topoII to a effective relevant target for topoisomerase poisons.