title: Histone deacetylase inhibition redistributes topoisomerase IIβ from heterochromatin to euchromatin.
abstract: 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.
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK. i.g.cowell@ncl.ac.uk
authors.forename: Ian G
authors.initials: IG
authors.lastname: Cowell
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papageorgiou
authors.forename: Kay
authors.initials: K
authors.lastname: Padget
authors.forename: Gary P
authors.initials: GP
authors.lastname: Watters
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Austin
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D022041:Euchromatin / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D021381:Protein Transport / Q000187:drug effects
chemical_list: C000715593:CBX1 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D022041:Euchromatin; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000090266:Chromobox Protein Homolog 5; C012589:trichostatin A; D005047:Etoposide; D004247:DNA; D006655:Histone Deacetylases; D004250:DNA Topoisomerases, Type II