Human topoisomerase II and mitochondrial topoisomerases

Human topoisomerase II (isoforms alpha and beta) and mitochondrial topoisomerases (such as TOP1MT and TOP3A) are essential enzymes that manage the topological state of nuclear and mitochondrial DNA (NIH, 2018; OUP, 2022). Topoisomerase II alpha (TOP2A) is primarily expressed in proliferating cells and is crucial for DNA replication and chromosome segregation, while Topoisomerase II beta (TOP2B) is expressed in both dividing and post-mitotic cells, playing a key role in transcriptional regulation (NIH, 2020; ResearchGate, 2020). Mitochondrial topoisomerases, particularly TOP1MT, are nuclear-encoded enzymes that localize to the mitochondria to maintain the integrity and supercoiling of the mitochondrial genome (mtDNA) (Journal of Cell Science, 2025; NIH, 2025). These enzymes are major targets for anticancer therapy; topoisomerase poisons like etoposide and doxorubicin stabilize the transient DNA-enzyme cleavage complex, resulting in lethal DNA damage and cell death (Wikipedia; NIH, 2020). However, the clinical use of these drugs is often limited by significant safety concerns, including TOP2B-mediated cardiotoxicity and the risk of secondary leukemias (NIH, 2020). Recent studies also highlight the importance of mitochondrial topoisomerases in maintaining cellular energy metabolism and their potential as targets in viral infections and neurodegenerative disorders (NIH, 2021).

Other names

DNA topoisomerase 2-alphaDNA topoisomerase 2-betaDNA topoisomerase I, mitochondrialDNA topoisomerase 3-alphaTOP2ATOP2BTOP1MTTOP3AType II topoisomeraseMitochondrial topoisomerase

Topoisomerase poisons (e.g., etoposide, doxorubicin) stabilize the covalent enzyme-DNA cleavage complex, preventing DNA religation and leading to lethal double-strand breaks. Catalytic inhibitors (e.g., dexrazoxane) interfere with the enzyme's catalytic cycle, such as ATPase activity or DNA binding, without inducing immediate DNA breaks.