DNA topoisomerase 2 (TOP2) (TOP2)

DNA topoisomerase 2 is a vital nuclear enzyme responsible for managing DNA topology by creating transient double-strand breaks to resolve knots and tangles during essential processes like replication, transcription, and chromosome segregation (UniProt, 2023). In humans, it exists as two distinct isoforms: TOP2A, which is highly expressed in proliferating cells and essential for mitosis, and TOP2B, which is expressed constitutively across all cell types and involved in transcription (Nature Reviews Cancer, 2009). This enzyme is a primary therapeutic target for several classes of potent anticancer drugs, including anthracyclines and epipodophyllotoxins, which act as topoisomerase poisons by trapping the enzyme in a covalent complex with DNA (StatPearls, 2023). This stabilization prevents DNA religation, leading to the accumulation of double-strand breaks and subsequent apoptosis in rapidly dividing cancer cells. However, the interaction with TOP2B in non-proliferating tissues, such as cardiomyocytes, is a major driver of dose-limiting toxicities like congestive heart failure (Nature Medicine: Zhang et al., 2012). Consequently, DNA topoisomerase 2 remains a cornerstone of chemotherapy while presenting significant challenges regarding long-term safety and the risk of secondary malignancies.

Other names

Topoisomerase IIDNA topoisomerase (ATP-hydrolyzing)TOP2ATOP2BDNA topoisomerase IICleavable complex

Topoisomerase II inhibitors primarily act as poisons by stabilizing the transient covalent DNA-enzyme cleavage complex, which prevents DNA religation and leads to the accumulation of lethal double-strand breaks (StatPearls, 2023). Alternatively, catalytic inhibitors interfere with the enzyme's biochemical activity, such as ATP binding or DNA strand passage, without inducing immediate DNA damage (Nature Reviews Cancer, 2009).