Publication:
TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.

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Date

2020-05-05

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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

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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.

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MeSH Terms

Androgens
Animals
Cell Line
Cell Proliferation
Chromosome Breakage
DNA Breaks, Double-Stranded
DNA End-Joining Repair
DNA-Binding Proteins
Epithelial Cells
G1 Phase Cell Cycle Checkpoints
Genomic Instability
Histones
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphoric Diester Hydrolases
Prostate
Prostatic Neoplasms
RNA, Small Interfering
Receptors, Androgen

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Keywords

DNA double-strand break, TDP2, androgen, atypical epithelial hyperplasia, prostatic intraepithelial neoplasia, topoisomerase 2

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