Roles of the C-terminal domains of topoisomerase II? and topoisomerase II? in regulation of the decatenation checkpoint.

ABSTRACT: Topoisomerase (topo) II? and II? 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?, as previously reported, but also by topo II?. 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? and Y656 in topo II?. Deletion of most of the CTD of topo II?, 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?, while preserving the NLS, and mutation of Y640 in topo II? and Y656 in topo II? inhibits these activities. Structural studies suggest that the differential impact of the CTD on topo II? and topo II? 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? and topo II? cooperate to maintain genome stability, which may be distinctly modulated by their CTDs.

SUBMITTER: Kozuki T 

PROVIDER: S-EPMC5449615 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature