TPH2
DNA topoisomerase 1 (TOP1) is an essential enzyme in humans that is encoded by the TOP1 gene. This enzyme plays a critical role in DNA replication, transcription, and chromosomal segregation by relieving torsional strain in the DNA helix.
Function[edit | edit source]
DNA topoisomerase 1 is responsible for cutting one strand of a DNA double helix, allowing it to unwind, and then re-ligating the strand. This process is crucial for the relaxation of supercoiled DNA, which is necessary for various cellular processes such as DNA replication, transcription, and chromosome segregation.
TOP1 acts by creating a transient single-strand break in the DNA, allowing the DNA to rotate around the unbroken strand, thus relieving the torsional stress. After the relaxation, the enzyme re-ligates the broken strand, restoring the integrity of the DNA molecule.
Clinical Significance[edit | edit source]
Mutations in the TOP1 gene can lead to various genetic disorders and have been implicated in the development of certain cancers. TOP1 is also a target for anticancer drugs such as topotecan and irinotecan, which inhibit the enzyme's activity, leading to DNA damage and cell death in rapidly dividing cancer cells.
Mechanism of Action[edit | edit source]
TOP1 binds to DNA and introduces a transient single-strand break by forming a covalent bond with the 3' phosphate end of the DNA. This allows the DNA to rotate and relieve supercoiling. The enzyme then reseals the break, restoring the DNA to its original state. This process is ATP-independent and relies on the intrinsic energy of the supercoiled DNA.
Structure[edit | edit source]
The structure of TOP1 consists of several domains, including a core domain that binds DNA, a linker domain, and a C-terminal domain that is involved in the catalytic activity. The enzyme's active site contains a tyrosine residue that forms a covalent bond with the DNA during the cleavage process.
Research and Development[edit | edit source]
Research on TOP1 has focused on understanding its role in cellular processes and its potential as a therapeutic target. Inhibitors of TOP1 are used in chemotherapy to treat various cancers, and ongoing research aims to develop more effective and selective inhibitors.
Also see[edit | edit source]
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Contributors: Prab R. Tumpati, MD