DNA topoisomerase II alpha and beta (TOP2A and TOP2B)

DNA topoisomerase II alpha and beta are essential ATP-dependent enzymes that regulate the topological states of DNA during vital cellular processes. They function as homodimers, introducing transient double-stranded breaks in DNA to relieve torsional strain, decatenate replicated chromosomes, and manage supercoiling. The alpha isoform (TOP2A) plays a critical role in cell division and chromosome segregation, while the beta isoform (TOP2B) is important for transcriptional regulation and neural development. Both enzymes are frontline therapeutic targets in oncology, where their inhibition, particularly by chemotherapeutic agents such as etoposide and doxorubicin, induces cytotoxic DNA damage. Mutations in these enzymes are linked to various diseases, including cancers, immunodeficiencies, and neurological disorders, and can also confer drug resistance. Their clinical use as drug targets is complicated by significant safety concerns, notably cardiotoxicity and the risk of therapy-related secondary malignancies.

Other names

Topoisomerase IITopo IITOP2α (alpha)TOP2β (beta)DNA topoisomerase IIAtype II topoisomerase

Inhibition of catalytic activity, leading to DNA double-strand breaks (e.g., by poisons such as etoposide and doxorubicin); Catalytic inhibition by interfering with ATPase activity (e.g., bisdioxopiperazines such as ICRF-193); Topoisomerase poisons stabilize the enzyme-DNA cleavage complex, preventing re-ligation and resulting in cytotoxic double-strand DNA breaks