DNA topoisomerases II (TOP2) are peculiar enzymes (TOP2α and TOP2β) that modulate the conformation of DNA by momentarily breaking double-stranded DNA to allow another strand to pass through, and then rejoins the DNA phosphodiester backbone. TOP2α and TOP2β play vital roles in nearly all events involving DNA metabolism, including DNA transcription, replication, repair, and chromatin remodeling. Beyond these vital functions, TOP2 enzymes are therapeutic targets for various anticancer drugs, termed TOP2 poisons, such as teniposide, etoposide, and doxorubicin. These drugs exert their antitumor activity by inhibiting the activity of TOP2–DNA cleavage complexes (TOP2ccs) containing DNA double-strand breaks (DSBs), subsequently leading to the degradation of TOP2 by the 26S proteasome, thereby exposing the DSBs and eliciting a DNA damage response. Failure of the DSBs to be appropriately repaired leads to genomic instability. Due to this mechanism, patients treated with TOP2-based drugs have a high incidence of secondary malignancies and cardiotoxicity. While the cytotoxicity associated with TOP2 poisons appears to be TOP2α-dependent, the DNA sequence rearrangements and formation of DSBs appear to be mediated primarily through TOP2β inhibition, likely due to the differential degradation patterns of TOP2α and TOP2β. Research over the past few decades has shown that under various conditions, the ubiquitin–proteasome system (UPS) and the SUMOylation pathway are primarily responsible for regulating the stability and activity of TOP2 and are therefore critical regulators of the therapeutic effect of TOP2-targeting drugs. In this review, we summarize the current progress on the regulation of TOP2α and TOP2β by ubiquitination and SUMOylation. By fully elucidating the basic biology of these essential and complex molecular mechanisms, better strategies may be developed to improve the therapeutic efficacy of TOP2 poisons and minimize the risks of therapy-related secondary malignancy.

DNA 拓扑异构酶 II (TOP2) 是一种特殊的酶（TOP2α 和 TOP2β），它们通过瞬间破坏双链 DNA 以允许另一条链通过，然后重新加入 DNA 磷酸二酯骨架来调节 DNA 的构象。TOP2α 和 TOP2β 在几乎所有涉及 DNA 代谢的事件中都起着至关重要的作用，包括 DNA 转录、复制、修复和染色质重塑。除了这些重要功能之外，TOP2 酶还是各种抗癌药物（称为 TOP2 毒物，如替尼泊苷、依托泊苷和多柔比星）的治疗靶点。这些药物通过抑制含有 DNA 双链断裂 (DSB) 的 TOP2-DNA 裂解复合物 (TOP2ccs) 的活性发挥其抗肿瘤活性，随后导致 TOP2 被 26S 蛋白酶体降解，从而暴露 DSB 并引发 DNA 损伤回复。DSB 未能得到适当修复会导致基因组不稳定。由于这种机制，接受 TOP2 药物治疗的患者继发性恶性肿瘤和心脏毒性的发生率很高。虽然与 TOP2 毒物相关的细胞毒性似乎是 TOP2α 依赖性的，但 DNA 序列重排和 DSB 的形成似乎主要通过 TOP2β 抑制介导，可能是由于 TOP2α 和 TOP2β 的不同降解模式。过去几十年的研究表明，在各种条件下，泛素-蛋白酶体系统 (UPS) 和 SUMO 化途径主要负责调节 TOP2 的稳定性和活性，因此是 TOP2 靶向药物治疗效果的关键调节因子. 在本次审查中，我们总结了目前通过泛素化和SUMOylation调节TOP2α和TOP2β的进展。通过充分阐明这些重要而复杂的分子机制的基础生物学，可以开发出更好的策略来提高 TOP2 毒物的治疗效果并最大限度地降低与治疗相关的继发性恶性肿瘤的风险。