DNA MINOR GROOVE-BINDING LIGANDS - A DIFFERENT CLASS OF MAMMALIAN DNATOPOISOMERASE-I INHIBITORS

Citation
Ay. Chen et al., DNA MINOR GROOVE-BINDING LIGANDS - A DIFFERENT CLASS OF MAMMALIAN DNATOPOISOMERASE-I INHIBITORS, Proceedings of the National Academy of Sciences of the United Statesof America, 90(17), 1993, pp. 8131-8135
Citations number
31
Categorie Soggetti
Multidisciplinary Sciences
ISSN journal
00278424
Volume
90
Issue
17
Year of publication
1993
Pages
8131 - 8135
Database
ISI
SICI code
0027-8424(1993)90:17<8131:DMGL-A>2.0.ZU;2-I
Abstract
A number of DNA minor groove-binding ligands (MGBLs) are known to exhi bit antitumor and antimicrobial activities. We show that DNA topoisome rase (Topo) I may be a pharmacological target of MGBLs. In the presenc e of calf thymus Topo I, MGBLs induced limited but highly specific sin gle-strand DNA breaks. The 3' ends of the broken DNA strands are coval ently linked to Topo I polypeptides. Protein-linked DNA breaks are rea dily reversed by a brief heating to 65-degrees-C or the addition of 0. 5 M NaCl. These results suggest that MGBLs, like camptothecin, abort T opo I reactions by trapping reversible cleavable complexes. The sites of cleavage induced by MGBLs are distinctly different from those induc ed by camptothecin. Two of the major cleavage sites have been sequence d and shown to be highly A+T-rich, suggesting the possible involvement of a Topo I-drug-DNA ternary complex at the sites of cleavage. Differ ent MGBLs also exhibit varying efficiency in inducing Topo I-cleavable complexes, and the order of efficiency is as follows: Hoechst 33342 a nd 33258 >> distamycin A > berenil > netropsin. The lack of correlatio n between DNA binding and cleavage efficiency suggests that, in additi on to binding to the minor grooves of DNA, MGBLs must also interact wi th Topo I in trapping Topo I-cleavable complexes.