Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA–protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.

人类拓扑异构酶由六种酶组成：两种 IB 型（TOP1 和线粒体 TOP1 (TOP1MT)、两种 IIA 型（TOP2A 和 TOP2B）和两种 IA 型（TOP3A 和 TOP3B）拓扑异构酶。在这篇综述中，我们讨论了它们的生物化学及其作用）在转录、DNA 复制和染色质重塑中的作用，并强调在理解 TOP3A 和 TOP3B 方面取得的最新进展。由于最近在通过染色质环和拓扑关联域 (TAD) 阐明基因组的高阶组织方面取得了进展，我们整合了拓扑异构酶与基因组组织的功能 我们还讨论了不可逆拓扑异构酶切割复合物 (TOPccs) 的生理和病理形成，因为它们产生与 DNA 断裂相结合的拓扑异构酶 DNA-蛋白质交联 (TOP-DPC)。我们讨论了越来越多的修复 TOP-DPC 的冗余途径，以及这些途径中的缺陷，这些途径越来越被认为是导致神经系统疾病和癌症的基因组损伤的来源。