DNA minor groove-binding ligands: A different class of mammalian DNA topoisomerase I inhibitors

Allan Y. Chen, Chiang Yu, Barbara Gatto, Leroy F. Liu

Research output: Contribution to journalArticlepeer-review

312 Citations (Scopus)


A number of DNA minor groove-binding ligands (MGBLs) are known to exhibit antitumor and antimicrobial activities. We show that DNA topoisomerase (Topo) I may be a pharmacological target of MGBLs. In the presence of calf thymus Topo I, MGBLs induced limited but highly specific single-strand DNA breaks. The 3′ ends of the broken DNA strands are covalently linked to Topo I polypeptides. Protein-linked DNA breaks are readily reversed by a brief heating to 65°C or the addition of 0.5 M NaCl. These results suggest that MGBLs, like camptothecin, abort Topo I reactions by trapping reversible cleavable complexes. The sites of cleavage induced by MGBLs are distinctly different from those induced by camptothecin. Two of the major cleavage sites have been sequenced 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. Different MGBLs also exhibit varying efficiency in inducing Topo I-cleavable complexes, and the order of efficiency is as follows: Hoechst 33342 and 33258 ≫ distamycin A > berenil > netropsin. The lack of correlation between DNA binding and cleavage efficiency suggests that, in addition to binding to the minor grooves of DNA, MGBLs must also interact with Topo I in trapping Topo I-cleavable complexes.

Original languageEnglish
Pages (from-to)8131-8135
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
Publication statusPublished - Sept 1 1993
Externally publishedYes

ASJC Scopus subject areas

  • General


Dive into the research topics of 'DNA minor groove-binding ligands: A different class of mammalian DNA topoisomerase I inhibitors'. Together they form a unique fingerprint.

Cite this