Topoisomerase II inhibition suppresses the proliferation of telomerase-negative cancers
Journal
Cellular and Molecular Life Sciences
Journal Volume
72
Journal Issue
9
Pages
1825-1837
Date Issued
2015
Author(s)
Abstract
Telomere maintenance is required for chromosome stability, and telomeres are typically elongated by telomerase following DNA replication. In both tumor and yeast cells that lack telomerase, telomeres are maintained via an alternative recombination mechanism. Previous studies have indicated that yeast Sgs1 and Top3 may work together to remove highly negative supercoils that are generated from recombination. However, the mechanism by which cells eradicate highly positive supercoils during recombination remains unclear. In the present study, we demonstrate that TOP2 is involved in telomere-telomere recombination. Disturbance of telomeric structure by RIF1 or RIF2 deletion alleviates the requirement for TOP2 in telomere-telomere recombination. In human telomerase-negative alternative lengthening of telomere (ALT) cells, TOP2α or TOP2β knockdown decreases ALT-associated PML bodies, increases telomere dysfunction-induced foci and triggers telomere shortening. Similar results were observed when ALT cells were treated with ICRF-193, a TOP2 inhibitor. Importantly, ICRF-193 treatment blocks ALT-associated phenotypes in vitro, causes telomere shortening, and inhibits ALT cell proliferation in mice. Taken together, these findings imply that TOP2 is involved in the ALT pathway, perhaps by resolving the highly positive supercoil structure at the front of the helicase. Inhibition of topoisomerase II may be a promising therapeutic approach that can be used to prevent cell proliferation in ALT-type cancer cells. ? 2014 Springer Basel.
SDGs
Other Subjects
4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; DNA topoisomerase (ATP hydrolysing); gyrase inhibitor; piperazine derivative; telomerase; telomere binding protein; animal; cell proliferation; drug effects; gene deletion; gene silencing; genetics; human; metabolism; mouse; Neoplasms; pathology; telomere homeostasis; tumor cell line; Animals; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type II; Gene Deletion; Gene Knockdown Techniques; Humans; Mice; Neoplasms; Piperazines; Telomerase; Telomere Homeostasis; Telomere-Binding Proteins; Topoisomerase II Inhibitors
Type
journal article