Al Mahmud, Md RaselIshii, KenichiroBernal-Lozano, CristinaDelgado-Sainz, IreneToi, MasakazuAkamatsu, ShusukeFukumoto, ManabuWatanabe, MasatoshiTakeda, ShunichiCortés-Ledesma, FelipeSasanuma, Hiroyuki2023-02-082023-02-082020-05-05http://hdl.handle.net/10668/15356Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double-strand breaks (DSBs), where TOP2 homodimers covalently bind to 5' DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase-2 (TDP2) removes 5' TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0 /G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0 /G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen-induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2-deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/DNA double-strand breakTDP2androgenatypical epithelial hyperplasiaprostatic intraepithelial neoplasiatopoisomerase 2AndrogensAnimalsCell LineCell ProliferationChromosome BreakageDNA Breaks, Double-StrandedDNA End-Joining RepairDNA-Binding ProteinsEpithelial CellsG1 Phase Cell Cycle CheckpointsGenomic InstabilityHistonesHumansMaleMiceMice, Inbred C57BLMice, KnockoutPhosphoric Diester HydrolasesProstateProstatic NeoplasmsRNA, Small InterferingReceptors, Androgenresearch article32277721open access10.1111/gtc.127701365-2443PMC7497232https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/gtc.12770https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497232/pdf