Topoisomerase

Topoisomerase

Overview of DNA topology

Topoisomerases are enzymes that participate in the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double-helical structure. During processes such as DNA replication and transcription, the DNA helix must be unwound, which can lead to supercoiling. Topoisomerases resolve these topological issues by inducing transient breaks in the DNA strands, allowing them to be untangled or relaxed.

Types of Topoisomerases

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

Type I Topoisomerases

Type I topoisomerase catalytic cycle

Type I topoisomerases cut one of the two strands of DNA, 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 are further divided into Type IA and Type IB, each with distinct mechanisms and structural features.

Type II Topoisomerases

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. These enzymes are essential for processes such as chromosome segregation during cell division.

Mechanism of Action

Topoisomerases function through a series of steps involving DNA cleavage, passage, and religation. The catalytic mechanism involves the formation of a transient covalent bond between the enzyme and the DNA, which facilitates the controlled breakage and rejoining of DNA strands.

Catalytic mechanisms of topoisomerases

Biological Functions

Topoisomerases play critical roles in various cellular processes:

• DNA Replication: They prevent the overwinding of DNA ahead of the replication fork.
• Transcription: They resolve supercoils generated during the transcription of DNA into RNA.
• Chromosome Condensation: They are involved in the condensation and decondensation of chromosomes during cell division.

Topological ramifications of DNA replication and transcription

Inhibitors and Poisons

Topoisomerase inhibitors are important tools in cancer therapy. They interfere with the enzyme's ability to manage DNA topology, leading to DNA damage and cell death.

Bacterial Topoisomerase Poisons

Bacterial topoisomerase poisons

These compounds target bacterial topoisomerases, making them effective antibiotics. Examples include quinolones and fluoroquinolones.

Eukaryotic Topoisomerase Inhibitors

Eukaryotic topoisomerase poisons and inhibitors

In eukaryotes, topoisomerase inhibitors are used in chemotherapy. Drugs such as etoposide and doxorubicin target topoisomerase II, while camptothecin targets topoisomerase I.

DNA Damage and Repair

Topoisomerase activity can lead to DNA double-strand breaks (DSBs), which are repaired by cellular mechanisms such as non-homologous end joining (NHEJ).

DNA DSB TOP2B PARP-1 complex with NHEJ enzymes

Related Pages

• DNA replication
• Transcription (biology)
• Chromosome segregation
• Antibiotics
• Chemotherapy