Type I DNA topoisomerase

Type I DNA topoisomerase is a crucial enzyme that plays a significant role in the DNA replication and transcription processes by altering the topological states of DNA. This enzyme works by transiently breaking one strand of a DNA double helix, allowing the unbroken strand to pass through the break, and then rejoining the broken strand. This action helps to relieve the supercoiling that can occur as the DNA double helix unwinds, ensuring the smooth progression of replication and transcription processes.

Function

Type I DNA topoisomerases are essential for solving topological problems associated with DNA replication, transcription, recombination, and chromosome segregation. They are involved in the relaxation of supercoiled DNA, thereby facilitating the necessary unwinding and rewinding of the DNA strands. This relaxation is critical for the access of various proteins and enzymes involved in DNA processing.

Mechanism

The mechanism of action of type I DNA topoisomerases involves the cleavage of one strand of the DNA double helix. This cleavage allows the rotation of the cleaved strand around the intact strand, thereby relieving supercoils. After the tension is relieved, the enzyme re-ligates the cleaved DNA strand, restoring the integrity of the DNA molecule. This process does not require ATP (Adenosine Triphosphate), distinguishing it from type II DNA topoisomerases, which work on both strands of the DNA and require ATP.

Classification

Type I DNA topoisomerases are classified into two main subtypes based on their structural and mechanistic differences: type IA and type IB. Type IA topoisomerases, such as Topoisomerase III, typically bind to single-stranded DNA and pass a second single-stranded DNA through the break. In contrast, type IB topoisomerases, such as Topoisomerase I, act on double-stranded DNA and induce a transient single-strand break.

Clinical Significance

Type I DNA topoisomerases are targets for certain antibiotics and anticancer drugs. For example, topotecan and irinotecan are topoisomerase I inhibitors used in cancer therapy. These drugs work by stabilizing the transient break caused by the enzyme, preventing the re-ligation of the DNA strand and leading to DNA damage, which can kill rapidly dividing cancer cells.

Safety and Side Effects

While topoisomerase inhibitors are effective in treating certain cancers, they can also lead to side effects due to their impact on normal cells. The most common side effects include nausea, vomiting, and a decrease in blood cell counts, which can lead to an increased risk of infection.

Research Directions

Ongoing research aims to develop more selective and less toxic topoisomerase inhibitors. Scientists are also exploring the role of type I DNA topoisomerases in various diseases beyond cancer, including neurological disorders and infectious diseases, to identify potential new therapeutic targets.

Type I DNA topoisomerase Resources
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