Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy.
Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy.
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DOI：
10.1007/s11033-021-06665-7
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发表时间：
2021-09
影响因子：
2.8
通讯作者：
Shu J
中科院分区：
文献类型：
--
作者：
Ma Y;North BJ;Shu J
DNA拓扑异构酶II （TOP2）是一种特殊的酶（TOP2α和TOP2β），它通过暂时破坏双链DNA以允许另一条DNA链通过，然后重新连接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。除了这些重要功能外，TOP2酶还是各种抗癌药物的治疗靶点，这些药物被称为TOP2毒药，如天尼泊苷、依托泊苷和阿霉素。这些药物通过抑制含有DNA双链断裂（dsb）的TOP2 - DNA切割复合物（TOP2ccs）的活性，进而导致26S蛋白酶体对TOP2的降解，从而暴露dsb并引发DNA损伤反应，从而发挥抗肿瘤活性。如果dsb不能得到适当的修复，就会导致基因组不稳定。由于这一机制，以top2为基础的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毒素相关的细胞毒性似乎依赖于TOP2α，但DNA序列重排和dsb的形成似乎主要通过TOP2β抑制介导，这可能是由于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（ubiquitin-proteasome system， UPS）和SUMOylation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。本文就TOP2α和TOP2β通过泛素化和sumo化调控的研究进展进行综述。通过充分阐明这些重要而复杂的分子机制的基本生物学，可以制定更好的策略来提高TOP2毒物的治疗效果，并最大限度地降低治疗相关继发性恶性肿瘤的风险。
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.
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作者：
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