Kozuki, TTKozukiChikamori, KKChikamoriSurleac, MDMDSurleacMicluta, MAMAMiclutaPetrescu, AJAJPetrescuNorris, EJEJNorrisElson, PPElsonHoeltge, GAGAHoeltgeGrabowski, DRDRGrabowskiPorter, ACGACGPorterGanapathi, RNRNGanapathiGanapathi, MKMKGanapathi2017-08-222017-05-022017-08-222017-05-02NUCLEIC ACIDS RESEARCH, 2017, 45 (10), pp.5995-60100305-1048http://hdl.handle.net/10044/1/49673Topoisomerase (topo) IIα and IIβ 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 IIα, as previously reported, but also by topo IIβ. 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 IIα and Y656 in topo IIβ. Deletion of most of the CTD of topo IIα, 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 IIβ, while preserving the NLS, and mutation of Y640 in topo IIα and Y656 in topo IIβ inhibits these activities. Structural studies suggest that the differential impact of the CTD on topo IIα and topo IIβ 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 IIα and topo IIβ cooperate to maintain genome stability, which may be distinctly modulated by their CTDs.© 2017 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyDNA TOPOISOMERASESTRUCTURAL BASISG(2) CHECKPOINTCELL-LINESEXPRESSIONDIFFERENTIATIONTRANSCRIPTIONMECHANISMSRESISTANTISOFORMS05 Environmental Sciences06 Biological Sciences08 Information And Computing SciencesDevelopmental BiologyJournal Articlehttps://www.dx.doi.org/10.1093/nar/gkx3251362-4962