Topological Differences in the Interaction of Human DNA Topoisomerase I with DNA–Histone Complexes Modified by cis- and trans-DDP
Chemical and pharmaceutical bulletin
2 , cisplatin or cis-DDP) is an effective chemotherapeutic agent for the treatment of various neoplasms (Fig. 1) . The full mechanism of its anti-neoplastic activity has yet to be elucidated, however. Several molecular studies have demonstrated that the bifunctional coordinate bonds between cis-DDP and cellular DNA play some role in cell death. 1-3) Although the trans-isomer of cis-DDP also binds to cellular DNA, it has been shown to be clinically ineffective. 4) The reasons for this difference
... is unclear. 3,5,6) To explore the differences in antineoplastic activity between cis-and trans-DDP, we have been investigating the topological transformation of DNA structure by the reaction of cis-DDP-(trans-DDP)-modified DNA with DNA topoisomerase I (topo I). DNA topoisomerases serve critical functions in living cells in the regulation of DNA transcription and replication. 7) DNA topoisomerases alter DNA topology by breaking and rejoining the DNA phosphodiester backbone through a single-strand DNA passage mechanism. While it is clear that cis-DDP-modified chromatin interacts differently with DNA topoisomerases, it is unknown how this interaction specifically occurs. In a previous paper, we formed topologically distinct invariant DNAs -trefoil and catenane-by the reaction of cis-DDP-modified DNA with DNA topoisomerase. 8) Here, we aim to expand the results of the previous study to a histone-containing chromatin model. Recently, high-mobility group (HMG) domain proteins that bind specifically to the major cis-DDP DNA adducts have been reported. 9) In vitro, HMG proteins form more stable platinum DNA-protein complex with cis-DDP binding 526 We show that the trefoil, figure-eight knot, and mini circular closed DNA are formed by the reaction of cis-DDP-modified f fX174DNA-histone LNCaP complexes as a new nucleosome model with human DNA topoisomease I. The yields from cis-DDP-modified complexes were far higher than that of trans-DDP. The topologically-distinct invariant DNA such as the trefoil and figure-eight knot are not produced in the reaction of DNA topo I with f fX174DNA-histone LNCaP complexes that are not modified by platinum. Therefore, the anti-cancer activity of cis-DDP may be related to the production of the trefoil, figure-eight knot, and mini circular closed DNA forms in the living cell. We subsequently demonstrate that the yield mechanism and identification of the topologically-distinct invariant DNA can be explained by the topological method using a Jones polynomial and recombination through the topo I path intra-twisted looped DNA model. These results suggest that the distinguishing of anti-neoplastic activity of cis-and trans-DDP can be partially explained by the distinct topologies of DNA, trefoil, figure-eight knot, and mini circular closed DNA that they produce.