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

Abstract

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.

Keywords: DNA double-strand break; TDP2; androgen; atypical epithelial hyperplasia; prostatic intraepithelial neoplasia; topoisomerase 2.