Topoisomerase

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Overview of DNA topology

Topoisomerases are enzymes that play a crucial role in the DNA replication, transcription, and chromosome segregation processes by managing the topological states of DNA. These enzymes are essential for maintaining the structural integrity of DNA during cellular processes that involve the unwinding and rewinding of the DNA double helix.

Function

Topoisomerases are responsible for solving the topological problems that arise during DNA replication and transcription. As the DNA double helix unwinds, it creates tension and supercoiling ahead of the replication fork. Topoisomerases alleviate this tension by introducing transient breaks in the DNA strands, allowing the DNA to be untangled or relaxed.

Types of Topoisomerases

Topoisomerases are classified into two main types based on their mechanism of action:

Type I Topoisomerases

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Type I topoisomerase catalytic cycle

Type I topoisomerases cut one of the two strands of a DNA double helix, allowing the uncut strand to pass through the break before resealing the cut. This process changes the linking number of the DNA by one. Type I topoisomerases do not require ATP to function. They are further divided into Type IA and Type IB topoisomerases, each with distinct mechanisms and structural features.

Type II Topoisomerases

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Type II topoisomerase catalytic cycle

Type II topoisomerases cut both strands of the DNA helix simultaneously, allowing another segment of the double helix to pass through the break. This changes the linking number by two. Type II topoisomerases require ATP to function. They are essential for processes such as chromosome segregation during mitosis and meiosis.

Catalytic Mechanisms

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Catalytic mechanisms of topoisomerases

The catalytic mechanisms of topoisomerases involve the formation of a transient covalent bond between the enzyme and the DNA. This bond is formed between a tyrosine residue in the enzyme and the phosphate backbone of the DNA, allowing the DNA to be cleaved and rejoined in a controlled manner.

Biological Importance

Topoisomerases are vital for the proper functioning of cells. They prevent the overwinding or tangling of DNA, which can lead to genomic instability and cell death. During DNA replication, topoisomerases prevent the formation of supercoils that can impede the progress of the replication fork.

Topological Ramifications

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Topological ramifications of DNA replication and transcription

The topological challenges addressed by topoisomerases are critical during DNA replication and transcription. Without the action of these enzymes, the DNA would become too tightly coiled, preventing the necessary unwinding for these processes to occur efficiently.

Inhibitors and Poisons

Topoisomerases are targets for a variety of antibiotics and anticancer drugs. These inhibitors can stabilize the transient DNA-topoisomerase complex, preventing the re-ligation of the DNA strands and leading to DNA damage.

Bacterial Topoisomerase Poisons

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Bacterial topoisomerase poisons

Bacterial topoisomerase inhibitors, such as quinolones, are used as antibiotics. They target bacterial topoisomerases, leading to the accumulation of DNA breaks and cell death.

Eukaryotic Topoisomerase Poisons

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Eukaryotic topoisomerase poisons and inhibitors

In eukaryotes, topoisomerase inhibitors are used in cancer therapy. Drugs such as etoposide and doxorubicin target topoisomerase II, causing DNA damage in rapidly dividing cancer cells.

DNA Repair and Topoisomerases

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DNA DSB TOP2B PARP-1 complex with NHEJ enzymes

Topoisomerases are also involved in DNA repair processes. They can facilitate the repair of double-strand breaks by interacting with other repair proteins, such as PARP-1 and NHEJ enzymes.

Related Pages

• DNA replication
• Transcription (genetics)
• Chromosome segregation
• Antibiotics
• Cancer therapy