Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Laboratory of Genomic Integrity, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Nat Rev Mol Cell Biol. 2022 Jun;23(6):407-427. doi: 10.1038/s41580-022-00452-3. Epub 2022 Feb 28.
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.
两种类型 IB（TOP1 和线粒体 TOP1（TOP1MT）），两种类型 IIA（TOP2A 和 TOP2B）和两种类型 IA（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特性及其在转录、DNA 复制和染色质重塑中的作用，并强调了近年来在理解 TOP3A 和 TOP3B 方面取得的进展。由于通过染色质环和拓扑关联域（TAD）阐明基因组高级组织的最新进展，我们将拓扑异构酶的功能与基因组组织相结合。我们还讨论了不可逆拓扑异构酶切割复合物（TOPcc）的生理和病理形成，因为它们产生拓扑异构酶 DNA-蛋白质交联（TOP-DPC）与 DNA 断裂相结合。我们讨论了修复 TOP-DPC 的冗余途径的数量不断增加，以及这些途径的缺陷，这些缺陷越来越被认为是导致神经疾病和癌症的基因组损伤的来源。
