Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded 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 work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.

拓扑异构酶 II (topo II) 对于解开新复制的染色体至关重要。DNA 断开涉及一个双链体通过另一个双链体的物理通道，并取决于双链 DNA 断裂的瞬时形成，这是一线化疗药物用来杀死癌细胞的一个步骤。尽管抗拓扑 II 药物有效，但它们也会在正常细胞中引起细胞毒性副作用；深入了解 topo II 在不同的细胞环境中是如何受到监管的，对于提高它们的针对性使用至关重要。使用化学分馏和质谱法，我们发现 topo II 通过 TCA 循环受到代谢控制。我们表明 TCA 代谢物在体外刺激拓扑 II 活性，并且 TCA 通量水平调节细胞对抗拓扑 II 药物的敏感性体内。我们的工作揭示了 DNA 拓扑结构的控制与细胞代谢之间的意外联系，这一发现对 anti-topo II 疗法的临床应用产生了影响。