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Using energy to go downhill—a genoprotective role for ATPase activity in DNA topoisomerase II

Bandak, Afif F; Blower, Tim R; Nitiss, Karin C; Shah, Viraj; Nitiss, John L; Berger, James M

Using energy to go downhill—a genoprotective role for ATPase activity in DNA topoisomerase II Thumbnail


Authors

Afif F Bandak

Karin C Nitiss

Viraj Shah

John L Nitiss

James M Berger



Abstract

Type II topoisomerases effect topological changes in DNA by cutting a single duplex, passing a second duplex through the break, and resealing the broken strand in an ATP-coupled reaction cycle. Curiously, most type II topoisomerases (topos II, IV and VI) catalyze DNA transformations that are energetically favorable, such as the removal of superhelical strain; why ATP is required for such reactions is unknown. Here, using human topoisomerase IIβ (hTOP2β) as a model, we show that the ATPase domains of the enzyme are not required for DNA strand passage, but that their loss elevates the enzyme's propensity for DNA damage. The unstructured C-terminal domains (CTDs) of hTOP2β strongly potentiate strand passage activity in ATPase-less enzymes, as do cleavage-prone mutations that confer hypersensitivity to the chemotherapeutic agent etoposide. The presence of either the CTD or the mutations lead ATPase-less enzymes to promote even greater levels of DNA cleavage in vitro, as well as in vivo. By contrast, aberrant cleavage phenotypes of these topo II variants is significantly repressed when the ATPase domains are present. Our findings are consistent with the proposal that type II topoisomerases acquired ATPase function to maintain high levels of catalytic activity while minimizing inappropriate DNA damage.

Citation

Bandak, A. F., Blower, T. R., Nitiss, K. C., Shah, V., Nitiss, J., & Berger, J. (2023). Using energy to go downhill—a genoprotective role for ATPase activity in DNA topoisomerase II. Nucleic Acids Research, https://doi.org/10.1093/nar/gkad1157

Journal Article Type Article
Acceptance Date Nov 24, 2023
Online Publication Date Dec 1, 2023
Publication Date Dec 1, 2023
Deposit Date Dec 21, 2023
Publicly Available Date Dec 21, 2023
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1093/nar/gkad1157
Keywords Genetics
Public URL https://durham-repository.worktribe.com/output/2049483

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