%0 Journal Article
%A Al Mahmud, Md Rasel
%A Ishii, Kenichiro
%A Bernal-Lozano, Cristina
%A Delgado-Sainz, Irene
%A Toi, Masakazu
%A Akamatsu, Shusuke
%A Fukumoto, Manabu
%A Watanabe, Masatoshi
%A Takeda, Shunichi
%A Cortés-Ledesma, Felipe
%A Sasanuma, Hiroyuki
%T TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.
%D 2020
%U http://hdl.handle.net/10668/15356
%X 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 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.
%K DNA double-strand break
%K TDP2
%K androgen
%K atypical epithelial hyperplasia
%K prostatic intraepithelial neoplasia
%K topoisomerase 2
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