RT Journal Article
T1 TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.
A1 Al Mahmud, Md Rasel
A1 Ishii, Kenichiro
A1 Bernal-Lozano, Cristina
A1 Delgado-Sainz, Irene
A1 Toi, Masakazu
A1 Akamatsu, Shusuke
A1 Fukumoto, Manabu
A1 Watanabe, Masatoshi
A1 Takeda, Shunichi
A1 Cortés-Ledesma, Felipe
A1 Sasanuma, Hiroyuki
K1 DNA double-strand break
K1 TDP2
K1 androgen
K1 atypical epithelial hyperplasia
K1 prostatic intraepithelial neoplasia
K1 topoisomerase 2
AB 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.
YR 2020
FD 2020-05-05
LK http://hdl.handle.net/10668/15356
UL http://hdl.handle.net/10668/15356
LA en
DS RISalud
RD Apr 6, 2025