Topoisomerase I and II Expression in Recurrent Colorectal Cancer Cells: A Dubious Matter

DNA topoisomerases are enzymes which alter and modify the topology of double-stranded DNA, without changing the sequence of the structural units of DNA, namely the nucleotides. They act by transiently breaking and then religating the DNA helix. Therefore, they unwind the double helix, relaxing the supercoiled DNA, and they allow DNA strands or double helices to pass through each other. Topoisomerases are essential for replication, transcription, translation and recombination of DNA because, relaxing the double helix, they facilitate the function of other enzymes, like DNA and RNA polymerases. Topoisomerases are the magicians of the DNA world, as they practically solve all the topological problems occurring during every aspect of DNA metabolism (Gupta et al., 1995; Pommier et al., 1998; Stewart et al, 1998; Champoux et al., 2001; Burden et al., 1998; Kellner et al., 2003; Wang et al., 2002). The first topoisomerase discovered, in 1971, was E. coli topoisomerase I, originally known as ω protein (Wang, 1971). Next year there was the discovery of eukaryotic topoisomerase I in nuclei extract from secondary mouse-embryo cells (Champoux et al., 1972) In 1976, DNA gyrase (topoisomerse II) was purified from Escherichia coli cells (Gellert et al., 1976a). Topoisomerases have been categorized in two basic families, according to their structure and mechanism of action: type I topoisomerases and type II topoisomerases. Type I topoisomerases mediate transient breaks in one of the DNA strands. They are further classified in the subfamilies IA and IB. Type IA topoisomerases form a covalent intermediate with the 5’-phosphoryl end of DNA, while type IB topoisomerases form a covalent intermediate with the 3’-phosphoryl end of DNA (Champoux et al., 2001). On the other hand, type II topoisomersases transiently cleave both of the two DNA strands. They are also further classified in the subfamilies IIA and IIB on the basis of differences in their protein structure. In human and higher eukaryotic organisms, three groups of topoisomerases have been described. The first group includes topoisomerase I and mitochondrial DNA topoisomerase, which are type IB enzymes. The second group includes topoisomerases II┙ and II┚, which are type II enzymes. The third group, which was later discovered, includes topoisomerases III┙ and III┚, which are type ΙΑ enzymes (Lodge et al., 2000; Kwan et al., 2001; Hanai et al., 1996). Topoisomerase IV has also been described, a bacterial type II topoisomerase (Kato et al., 1990). More recently, topoisomerase V has been described, which is a prokaryotic counterpart to the eukaryotic topoisomerase I (Slesarev et al., 1994).