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Sequence‐selective DNA cleavage by a topoisomerase I poison, NB‐506
Author(s) -
Fukasawa Kazuhiro,
Komatani Hideya,
Hara Yoshikazu,
Suda Hiroyuki,
Okura Akira,
Nishimura Susumu,
Yoshinari Tomoko
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980105)75:1<145::aid-ijc22>3.0.co;2-e
Subject(s) - camptothecin , topoisomerase , cleavage (geology) , dna , biology , stereochemistry , chemistry , biochemistry , paleontology , fracture (geology)
An indolocarbazole compound, NB‐506, inhibits the activity of topoisomerase I by stabilizing the DNA‐topoisomerase I complex (cleavable complex). NB‐506 inhibited the re‐ligation step of topoisomerase I activity more potently than camptothecin or its derivative, topotecan. A cleavage assay using an end‐labeled fragment of DNA revealed that the pattern of cleavage induced by NB‐506 was different from that induced by camptothecin. The preferred cleavage sites of NB‐506 were found to be not only T but also A or C at the 3′‐terminus of the cleaved DNA (position −1), while the DNA cleavage sites of camptothecin always had T at position −1. At the 5′‐terminus of the cleaved DNA (position +1), NB‐506 showed a preference for G, which is a feature shared in common with camptothecin. Therefore, the difference in cleavage patterns was most likely due mainly to the preferred base at position −1. Moreover, the re‐ligation rate was significantly slower at NB‐506‐selective sites, which had C at position‐1, than at camptothecin‐selective sites or at sites cleaved by both NB‐506 and camptothecin. Our data suggest that NB‐506 is an unique topoisomerase I poison and that its potent inhibition of topoisomerase I is partly dependent on retardation of re‐ligation at sites selectively induced by NB‐506. Int. J. Cancer 75:145–150, 1998.© 1998 Wiley‐Liss, Inc.