DNA topoisomerase II alpha (Top2)

DNA topoisomerase II alpha Overview

DNA topoisomerase II alpha is an essential enzyme that manages DNA topology by catalyzing the passage of one double-stranded DNA segment through a transient break in another, utilizing ATP hydrolysis. It is crucial for chromosome segregation during mitosis, DNA replication, and transcription. In cancer cells, its high expression and indispensable role in cell proliferation make it a prominent therapeutic target, particularly for antineoplastic agents such as doxorubicin. Doxorubicin and related drugs act as "topoisomerase II poisons," stabilizing the DNA-enzyme cleavage complex and thereby generating lethal DNA double-strand breaks. While these drugs have transformed cancer treatment, their capacity to induce off-target DNA damage raises concerns, including therapy-related secondary cancers and organ toxicities. The enzyme's expression serves as a predictive biomarker for the efficacy of certain chemotherapies, and its inhibition underpins a major class of anti-cancer drugs.

Mechanism of Action

Topoisomerase II poisons (e.g., doxorubicin, etoposide) stabilize the enzyme-DNA cleavage complex, leading to double-strand DNA breaks and cell death. Some drugs (e.g., doxorubicin, mitoxantrone) also intercalate into DNA and interfere with Top2 function. Catalytic inhibitors (e.g., ICRF-187) prevent the enzyme's ATPase activity or block DNA strand passage without inducing DNA breaks.

Biological Functions

Safety Considerations

Interacting Drugs

Associated Biomarkers