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oai:repisalud.isciii.es:20.500.12105/253562025-12-18T13:01:21Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Al Mahmud, Md Rasel author Ishii, Kenichiro author Bernal-Lozano, Cristina author Delgado-Sainz, Irene author Toi, Masakazu author Akamatsu, Shusuke author Fukumoto, Manabu author Watanabe, Masatoshi author Takeda, Shunichi author Cortes-Ledesma, Felipe author Sasanuma, Hiroyuki author 2020-07 Androgens 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 G /G phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G /G phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G 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. Genes Cells . 2020 Jul;25(7):450-465. Genes to Cells 32277721 https://hdl.handle.net/20.500.12105/25356 DNA double-strand break TDP2 androgen atypical epithelial hyperplasia prostatic intraepithelial neoplasia topoisomerase 2 TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.