DNA topoisomerase II (Top2)

DNA topoisomerase II is an essential enzyme that manages the topology of double-stranded DNA by introducing transient double-strand breaks. This action allows it to resolve tangles and supercoils that arise during critical cellular processes such as replication, transcription, recombination, and chromosome segregation. The enzyme functions through a "strand passage" mechanism in which it cleaves both strands of a segment of DNA (the G-segment), passes another segment through the break (the T-segment), then reseals the break using energy from ATP hydrolysis. There are two main isoforms in humans—Top2α and Top2β—with distinct but overlapping roles; for example, Top2α is especially important during cell division. DNA topoisomerase II is a validated therapeutic target in oncology because its inhibition can induce cytotoxic double-strand breaks selectively in rapidly dividing cells. Many anticancer drugs act either by stabilizing the normally transient covalent complex between enzyme and cleaved DNA ("poisons") or by inhibiting its catalytic activity ("catalytic inhibitors"). However, targeting this enzyme carries risks including genotoxic side effects that can lead to secondary cancers due to misrepair of drug-induced breaks. Overall, DNA topoisomerase II plays indispensable roles in genome maintenance but also represents a vulnerability exploited by several classes of chemotherapeutic agents.[1][2][3][5][6][7][8][9]

Other names

Topoisomerase IIType II topoisomeraseTopo IIDNA gyrase (in bacteria, though this term is more specific to prokaryotic type IIA enzymes)

Poisons: Stabilize the covalent enzyme-DNA complex, leading to accumulation of double-strand breaks and cell death. Examples include etoposide, doxorubicin, mitoxantrone. Catalytic inhibitors: Inhibit the catalytic activity without generating increased levels of covalent complexes; mechanisms include ATP binding competition or prevention of DNA cleavage/religation.