- Type II topoisomerases are essential enzymes responsible for managing DNA topology in both prokaryotic and eukaryotic cells.
- They play a crucial role in DNA replication, transcription, recombination, and chromosome segregation by relieving supercoiling and resolving tangled DNA structures.
- Unlike type I topoisomerases, which cleave single DNA strands, type II topoisomerases cut both strands, allowing for efficient strand passage and topological adjustments.
- Type II topoisomerases are typically composed of multiple subunits and function through an ATP-dependent mechanism. The enzyme consists of distinct domains responsible for DNA cleavage, strand passage, ATP hydrolysis, and re-ligation.
- In bacteria, DNA gyrase and topoisomerase IV are the primary type II topoisomerases:
- DNA Gyrase – Introduces negative supercoils to maintain DNA flexibility and support replication.
- Topoisomerase IV – Resolves catenated DNA (interlinked daughter chromosomes), ensuring proper segregation after replication.
- In eukaryotes, type II topoisomerases include:
- Topoisomerase IIα – Essential for chromosome condensation and separation during mitosis.
- Topoisomerase IIβ – Plays a role in transcriptional regulation and DNA damage response.
- These enzymes function as homodimers or heterotetramers, depending on the organism, and require ATP hydrolysis for their strand-passage mechanism.
- Type II topoisomerases solve topological problems by introducing transient double-strand breaks, allowing another DNA segment to pass through, and subsequently resealing the break. This process is essential for:
- Supercoiling regulation – Prevents excessive DNA twisting that occurs during replication and transcription.
- Decatenation of chromosomes – Ensures proper separation of newly synthesized daughter DNA molecules.
- DNA damage response – Helps resolve DNA tangles that can lead to genomic instability.
- Their ATP-dependent mechanism ensures tight regulation of DNA topology, preventing the accumulation of supercoiling stress that could hinder cellular functions.
- Type II topoisomerases are major targets for both antibacterial and chemotherapeutic drugs:
- Fluoroquinolone antibiotics – Target bacterial DNA gyrase and topoisomerase IV, causing lethal DNA strand breaks.
- Topoisomerase inhibitors (anticancer drugs) – Compounds like etoposide and doxorubicin interfere with eukaryotic topoisomerase II, stabilizing cleaved DNA-enzyme complexes and triggering apoptosis in cancer cells.
- While these drugs effectively disrupt bacterial or cancer cell survival, resistance mechanisms such as mutations in topoisomerase genes and efflux pump activation pose challenges for treatment efficacy.
