Roles of the C-terminal domains of topoisomerase IIα and topoisomerase IIβ in regulation of the decatenation checkpoint

Topoisomerase (topo) II alpha and II beta maintain genome stability and are targets for anti-tumor drugs. In this study, we demonstrate that the decatenation checkpoint is regulated, not only by topo II alpha, as previously reported, but also by topo II beta. The decatenation checkpoint is most efficient when both isoforms are present. Regulation of this checkpoint and sensitivity to topo II-targeted drugs is influenced by the C-terminal domain (CTD) of the topo II isoforms and by a conserved non-catalytic tyrosine, Y640 in topo II alpha and Y656 in topo II beta. Deletion of most of the CTD of topo II alpha, while preserving the nuclear localization signal (NLS), enhances the decatenation checkpoint and sensitivity to topo II-targeted drugs. In contrast, deletion of most of the CTD of topo II beta, while preserving the NLS, and mutation of Y640 in topo II alpha and Y656 in topo II beta inhibits these activities. Structural studies suggest that the differential impact of the CTD on topo II alpha and topo II beta function may be due to differences in CTD charge distribution and differential alignment of the CTD with reference to transport DNA. Together these results suggest that topo II alpha and topo II beta cooperate to maintain genome stability, which may be distinctly modulated by their CTDs.