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Type II DNA Topoisomerases Cause Spontaneous Double-Strand Breaks in Genomic DNA

1
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan
2
Department of Applied Biosciences, College of Agriculture and Life Sciences, Kyungpook National University, Daegu 41566, Korea
3
The Institute for Cell and Molecular Biosciences, the Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
*
Author to whom correspondence should be addressed.
Genes 2019, 10(11), 868; https://doi.org/10.3390/genes10110868
Received: 30 September 2019 / Revised: 22 October 2019 / Accepted: 26 October 2019 / Published: 30 October 2019
(This article belongs to the Special Issue DNA Topoisomerases in Biology and Medicine)
Type II DNA topoisomerase enzymes (TOP2) catalyze topological changes by strand passage reactions. They involve passing one intact double stranded DNA duplex through a transient enzyme-bridged break in another (gated helix) followed by ligation of the break by TOP2. A TOP2 poison, etoposide blocks TOP2 catalysis at the ligation step of the enzyme-bridged break, increasing the number of stable TOP2 cleavage complexes (TOP2ccs). Remarkably, such pathological TOP2ccs are formed during the normal cell cycle as well as in postmitotic cells. Thus, this ‘abortive catalysis’ can be a major source of spontaneously arising DNA double-strand breaks (DSBs). TOP2-mediated DSBs are also formed upon stimulation with physiological concentrations of androgens and estrogens. The frequent occurrence of TOP2-mediated DSBs was previously not appreciated because they are efficiently repaired. This repair is performed in collaboration with BRCA1, BRCA2, MRE11 nuclease, and tyrosyl-DNA phosphodiesterase 2 (TDP2) with nonhomologous end joining (NHEJ) factors. This review first discusses spontaneously arising DSBs caused by the abortive catalysis of TOP2 and then summarizes proteins involved in repairing stalled TOP2ccs and discusses the genotoxicity of the sex hormones. View Full-Text
Keywords: topoisomerase II; genotoxicity; cell cycle; estrogen; breast cancer; transcription; BRCA1; BRCA2 topoisomerase II; genotoxicity; cell cycle; estrogen; breast cancer; transcription; BRCA1; BRCA2
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Morimoto, S.; Tsuda, M.; Bunch, H.; Sasanuma, H.; Austin, C.; Takeda, S. Type II DNA Topoisomerases Cause Spontaneous Double-Strand Breaks in Genomic DNA. Genes 2019, 10, 868.

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