Artículo
TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands
Autor/es | Al Mahmud, Md Rasel
Ishii, Kenichiro Bernal Lozano, Cristina Delgado Sainz, Irene Toi, Masakazu Akamatsu, Shusuke Fukumoto, Manabu Watanabe, Masatoshi Takeda, Shunichi Cortés Ledesma, Felipe Sasanuma, Hiroyuki |
Fecha de publicación | 2020 |
Fecha de depósito | 2020-10-13 |
Publicado en |
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Resumen | 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 ... 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. |
Identificador del proyecto | JP19am0101092
SAF2010-21017 SAF2013-47343-P SAF2014-55532-R CVI-7948 |
Cita | Al Mahmud, M.R., Ishii, K., Bernal Lozano, C., Delgado Sainz, I., Toi, M., Akamatsu, S.,...,Sasanuma, H. (2020). TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands. Genes to Cells, 25 (7), 450-465. |
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