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Nucleic Acids Research, 1984, Vol. 12, No. 15 6159-6168
© 1984

MOLECULAR BIOLOGY

Characterization of an adduct between CC-1065 and a defined oligodeoxynucleotide duplex

Donald R. Needham-VanDevanter1, Laurence H. Hurley1,*, Vincent L. Reynolds1, Nicole Y. Theriault2, Williams C. Krueger2 and Wendall Wierenga2

1Drug Dynamics Institute, College of Pharmacy, University of Texas Austin, TX 78712 2Cancer Research and Physical and Analytical Chemistry, Upjohn Company Kalamazoo, MI 49001

*To whom inquiries should be addressed

Received March 28, 1984. Revised June 10, 1984. Accepted June 10, 1984.

CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis. The drug binds covalently through N-3 of adenine and lies within the minor groove of DNA. Previous studies indicated that CC-1065 reacted with adenine in DNA to yield a thermally labile product that could be used to reveal its sequence specificity. These studies also provided insight into a DNA sequence (5'-CGGAGTTAGGGGCG-3') which should bind one molecule of CC-1065 in an unambiguous manner. This sequence, which contains the CC-1065 adenine binding site within the sequence 5'-TTA-3' was chemically synthesized together with the complementary strand. CC-1065 reacted with the oligoduplex to give an adduct that maintained the B-DNA form and had a final CD spectrum similar to those of the CC-1065 comp1exes formed with calf thymus DNA. The above l4mer was 5' end-labelled with 32P, annealed with its complementary strand, reacted with CC-1065 and heated. Drug-mediated strand breakage was evaluated on a sequencing gel. A single break occurred in the labelled strands to give a fragment that migrated as an 8.5mer; subsequent piperidine treatment produced a fragment that migrated as a 7mer, which is the size expected from the known binding of CC-1065 at adenine in 5'-TTA-3' sequences.


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