DNA topoisomerase I in oncology: Dr Jekyll or Mr Hyde?

Abstract

Mammalian DNA topoisomerase I is a multifunctional enzyme which is essential for embryonal development. In addition to its classical DNA nicking-closing activities which are needed for relaxation of supercoiled DNA, topoisomerase I can phosphorylate certain splicing factors. The enzyme is also involved in transcriptional regulation through its ability to associate with other proteins in the TFIID-, and possibly TFIIH-, transcription complexes, and is implicated in the recognition of DNA lesions. Finally, topoisomerase I is a recombinase which can mediate illegitimate recombination. A crucial reaction intermediate during relaxation of DNA is the formation of a DNA-topoisomerase I complex (the cleavable complex) where topoisomerase I is covalently linked to a 3 -end of DNA thereby creating a single stranded DNA break. Cleavable complexes are also formed in the vicinity of DNA lesions and in the presence of the antitumor agent, camptothecin. While formation of cleavable complexes may be necessary for the initial stages of the DNA damage response, these complexes are also potentially dangerous to the cell due to their ability to mediate illegitimate recombination, which can lead to genomic instability and oncogenesis. Thus the levels and stability of these complexes have to be strictly regulated. This is obtained by maintaining the enzyme levels relatively constant, by limiting the stability of the cleavable complexes through physical interaction with the oncogene suppressor protein p53 and by degradation of the topoisomerase I by the proteasome system. Emerging evidence suggest that these regulatory functions are perturbed in tumor cells, explaining at the same time why topoisomerase I activities so often are increased in certain human tumors, and why these cells are sensitized to the cytotoxic effects of camptothecins.