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.

中文翻译：

---

TDP2抑制了雄激素在前列腺上皮细胞中引起的基因组不稳定性。

雄激素通过激活拓扑异构酶2（TOP2）和调节靶基因的转录来刺激前列腺上皮细胞的增殖。TOP2通过瞬时产生双链断裂（DSB）来解决基因组DNA的纠缠，其中TOP2同型二聚体与5'DSB末端共价结合，称为TOP2-DNA裂解复合物（TOP2ccs）。当TOP2未能重新加入TOP2ccs产生停滞TOP2ccs，酪氨酰DNA磷酸二酯酶2（TDP2）从之前通过非同源末端连接（NHEJ）中，G中占主导地位的DSB修复途径的DNA双链断裂的连接停滞TOP2ccs去除5'TOP2加合物₀ / G ₁相。我们之前的研究表明，雌激素经常在G ₀ / G _1中产生停滞的TOP2cc阶段。在这里，我们证明了生理浓度的雄激素会在G ₁期诱导单个人前列腺癌细胞中的数个DSB ，而TDP2的丢失会导致有丝分裂染色体扩散中雄激素诱导的染色体断裂数增加五倍。腹膜内注射的雄激素即使在注射后20小时，也会在TDP2缺陷型小鼠的前列腺单个上皮细胞中诱导几种DSB。总之，雄激素的生理浓度具有很强的遗传毒性，很可能是通过产生停滞的TOP2cc而引起的。