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Nucleic Acids Res. 2017 Jun 2;45(10):5995-6010. doi: 10.1093/nar/gkx325.

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

Author information

1
Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
2
Department of Bioinformatics, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
3
Department of Cancer Pharmacology, Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA.
4
Clinical Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
5
Imperial College Faculty of Medicine, Hammersmith Hospital, London W10 ONN, UK.

Abstract

Topoisomerase (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.

PMID:
28472494
PMCID:
PMC5449615
DOI:
10.1093/nar/gkx325
[Indexed for MEDLINE]
Free PMC Article

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