Processing of DNA Topoisomerase II–DNA–Protein Crosslinks Associated With Anticancer Drugs

Abstract

During cell division and gene expression, the DNA double-helical structure unwinds, thereby generating torsional stress. DNA topoisomerases are enzymes that relieve this stress. During this process, topoisomerases form temporary covalent bonds with the phosphate backbone of DNA, generating DNA strand breaks and relieving torsional stress. Topoisomerases then dissociate from DNA after rejoining the DNA breaks. Torsional stress associated with replication or transcription is primarily relieved by topoisomerase I (TOP1) and II (TOP2). Some anticancer drugs targeting topoisomerases, known as topoisomerase poisons, trap the topoisomerase reaction intermediates and cause DNA strand breaks bearing topoisomerase–DNA–protein crosslinks (TOP–DPCs). TOP1 poisons, such as camptothecin, cause DNA single-strand breaks bearing TOP1–DPCs, which are converted to DNA double-strand breaks (DSBs) when they collide with DNA replication forks. In contrast, TOP2 poisons, such as etoposide, directly induce DSBs in TOP2–DPCs. However, to elicit a DSB response, TOP2–DPC must first be removed from the DSB ends. Cells possess various pathways to remove TOP2–DPC, and these pathways are thought to function in coordination depending on the situation. This review summarizes these sophisticated TOP2–DPC removal pathways and discusses the clinical applications of TOP2 poison as an anticancer drug, as well as the related challenges.