Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one DNA duplex through another and depends on the transient formation of double-strand DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our works reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with important ramifications for the clinical use of anti-topo II therapies.

中文翻译：

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通过TCA循环代谢物控制拓扑异构酶II活性和化学疗法的抑制作用

拓扑异构酶II（拓扑II）对于解开新复制的染色体至关重要。DNA脱链涉及一个DNA双链体通过另一双链体的物理通道，并取决于双链DNA断裂的瞬时形成，这是一线化学治疗技术用来杀死癌细胞的步骤。尽管抗拓扑Ⅱ药物是有效的，但它们也会在正常细胞中引起细胞毒性副作用。深入了解如何在不同的细胞环境中调节topo II对改善其靶向用途至关重要。使用化学分馏和质谱法，我们发现topo II在TCA循环中受代谢控制。我们表明，TCA代谢物在体外刺激了topo II的活性，TCA的水平在体内调节了细胞对抗拓扑II药物的敏感性。