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Department of Medicine, Division of Medical Oncology [R. F. D.] and Department of Biochemistry, [A. H. C., N. O.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146
The effects of serine phosphorylation on the DNA cleavage/religation equilibrium of topoisomerase II and the sensitivity of the enzyme to antineoplastic drugs were characterized. Both casein kinase II and protein kinase C were used for these studies. Each kinase incorporated a maximum of 
1.4 phosphate molecules per homodimer of topoisomerase II. When the enzyme was incubated with both kinases simultaneously, phosphate incorporation increased to 2.6 molecules/homodimer. In the absence of antineoplastic drugs, phosphorylation had only a slight effect on the DNA cleavage/religation equilibrium of topoisomerase II. However, in the presence of etoposide or 4'-(9-acridinylamino)methanesulfon-m-anisidide, phosphorylation attenuated the ability of drugs to stabilize enzyme-DNA cleavage complexes. Levels of drug-induced DNA cleavage products decreased 33% following phosphorylation of topoisomerase II by casein kinase II, 17% following modification by protein kinase C, and 50% following simultaneous phosphorylation of the enzyme by both kinases. This latter 50% reduction in DNA cleavage products correlated with an 2-fold increase in the apparent first order rate constant for DNA religation mediated by simultaneously modified topoisomerase II. These results strongly suggest that the sensitivity of topoisomerase II toward antineoplastic drugs can be modulated by altering the phosphorylation state of the enzyme.
1 This work was supported by National Institutes of Health Grants GM-33944 and DK-43325 and March of Dimes Birth Defects Foundation Basic Research Grant 1-1074. A. H. C. was a trainee under Grant 5 T32 CA-09582 from the National Cancer Institute. For a portion of this work, N. O. was supported by Faculty Research Award FRA-370 from the American Cancer Society.
2 Present address: Department of Medicine, Section of Hematology/Oncology, West Virginia University School of Medicine, Morgantown, WV 26506.
3 To whom correspondence and requests for reprints should be addressed, at Department of Biochemistry, 621 Light Hall, Vanderbilt University School of Medicine, Nashville, TN 37232-0146.
Received 10/18/91. Accepted 2/ 7/92.
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