DNA TOPOISOMERASES AS REPAIR ENZYMES - MECHANISM(S) OF ACTION AND REGULATION BY P53

DNA topoisomerases regulate the organization of DNA and are important targets for many clinically used antineoplastic agents. In addition, D NA topoisomerases modulate the cellular sensitivity toward a number of DNA damaging agents. Increased topoisomerase II activities were shown to contribute to the resistance of both nitrogen mustard- and cisplat in-resistant cells. Similarly, cells with decreased topoisomerase II l evels show increased sensitivity to cisplatin, carmustine, mitomycin C and nitrogen mustard. Recent studies propose that topoisomerases may be involved in damage recognition and DNA repair at several different levels including: 1) the initial recognition of DNA lesions; 2) DNA re combination; and 3) regulation of DNA structure. The stress-activated oncogene suppressor protein p53 can modulate the activity of at least three different human topoisomerases, either directly by molecular ass ociations or by transcriptional regulation. Since DNA topoisomerases h ave considerable recombinase activities, inappropriately activated top oisomerases in tumor cells lacking functional p53 may contribute to th e genetic instability of these cells.