topoisomerase (DNA) I; EC 188.8.131.52; TOP1; DNA topoisomerase 1; type I DNA topoisomerase; DNA topoisomerase 1;
Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand than undergoes passage around the unbroken strand thus removing DNA supercoils.
Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3)pre-mRNA in endothelial cells.
Topoisomerases are ubiquitously expressed enzymes that overcome topological problems in genomic DNA, which can result from DNA replication, transcription and repair. Common problems such as overwinding (positive supercoiling), knots and tangles are resolved by topoisomerases by catalysing the breaking of one or two
strands of DNA. Topoisomerase type I enzymes cut just one strand of the DNA double helix, and hence relax supercoiling of the DNA. Four genes encode Type I topoisomerases, which include nuclear topoisomerase I(TOP1) and mitochondrial topoisomerase I (TOP1MT). Type I enzymes can also be sub-divided into Types A and B based on their different catalytic mechanism for generating single DNA strand breaks. TOP1 and TOP1MT are both type 1B since they form 3'-phosphotyrosyl bonds. Camptothecin is a natural product inhibitor of TOP1 that has led to the discovery of derivatives that are clinically used anti-cancer drugs. Such inhibitors trap the enzyme in a cleavage complex with DNA. Type II topoisomerases (IIA and IIB) are particular important for the disentanglement of DNA, which is overcome by generating double stranded DNA breaks. Dysregulation of type II enzymes can therefore have a potentially significant genotoxic effect. There is a broad range of topoisomerase II inhibitors that are used clinically as anticancer agents.