Histone deacetylase inhibition redistributes topoisomerase II? 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 II? (topoII?) is also concentrated in heterochromatic regions. Similarly, a detergent-resistant fraction of topoII? is associated with heterochromatin in human cell lines. Treatment with TSA displaced topoII? from the heterochromatin with similar kinetics to the displacement of HP1?. 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? appears to be the major target for most topoisomerase poisons, histone deacetylase-mediated potentiation of these drugs is dependent on topoII?. We find that while prior treatment with TSA did not increase the quantity of etoposide-mediated topoII?-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 topoII? converts this isoform of topoII to a effective relevant target for topoisomerase poisons.

SUBMITTER: Cowell IG 

PROVIDER: S-EPMC3104810 | biostudies-other | 2011 Jan-Feb

REPOSITORIES: biostudies-other