Topoisomerases are a family of enzymes that catalyze the unwinding and unknotting of DNA sequences. By introducing transient \'nicks\', these enzymes can relieve the topological pile-up of DNA that is caused by processes such as replication and transcription. DNA Topoisomerase I (Topo1; EC. 5.99.1.2) regulates the overwinding or underwinding of DNA in an ATP-independent manner. It binds to single-stranded DNA and cuts the phosphate backbone of the DNA. This intermediate break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed again. Since the overall chemical composition and connectivity of the DNA do not change, the tangled and untangled DNAs are chemical isomers, differing only in their global topology.In slight contrast, topoisomerase IV (Topo IV; EC 5.99.1.3) is an essential ATP-dependent type II topoisomerase that transports one segment of DNA through a transient double-strand break in a second segment of DNA. In vivo, Topo IV unlinks catenated chromosomes before cell division and relaxes positive supercoils generated during DNA replication. Topoisomerase inhibitors work by interfering with mammalian-type eukaryotic topoisomerases in cancer cells. This induces breaks in the DNA that ultimately lead to programmed cell death (apoptosis). However, this DNA-damaging effect, outside of its potentially curative properties, may also lead to secondary neoplasms in the patient.