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A Putative Role for Nicotinamide Adenine Dinucleotide-promoted Nuclear Protein Modification in the Antitumor Activity of N-Methyl-N-nitrosourea¹

Biochemistry Department [M. E. S., D. W. M., S. S.] and Division of Medical Oncology [P. S.], Vincent T. Lombardi Cancer Research Canter, Georgetown University, School of Medicine, Washington, D. C. 20007

Incubation of HeLa cells with the anticancer agent N-methyl-N-nitrosourea (MNU) results in: (a) depression of intracellular nicotinamide adenine dinucleotide levels; (b) stimulation of the chromatin-associated, chromosomal protein-modifying enzyme polyadenosine diphosphoribose [poly(ADP-ribose)] polymerase, which uses nicotinamide adenine dinucleotide as substrate; and (c) some fragmentation of cellular DNA. DNase treatment of HeLa nuclei in vitro also stimulates poly(ADP-ribose) polymerase activity, but not in nuclei derived from MNU-treated cells unless they have been subsequently incubated to allow for recovery from MNU damage. DNA polymerase activity is stimulated in vitro by poly(ADP) ribosylation of nuclear proteins. By using intact nuclei derived from MNU-treated HeLa cells, the repair via elongation of single-strand DNA breaks is demonstrated in vitro. This repair is dependent on DNA polymerase activity and is enhanced by adenosine diphosphate ribosylation of histones. Inhibition of poly(ADP-ribose) polymerase with nicotinamide results in extensive degradation of MNU-damaged DNA. Taken as a whole, these results suggest that poly(ADP-ribose) polymerase may play a role in the repair of alkylation damage to cellular DNA and that the inhibition of this enzyme in vivo might be exploited to potentiate the antitumor and carcinogenic activities of MNU.

¹ This work was supported by Grants CA 13195 and CA 17583 awarded by the National Cancer Institute, Department of Health, Education and Welfare, and Mazor Memorial Grant for Cancer Research CH-13 from the American Cancer Society.

² Submitted to the Department of Biochemistry in partial fulfillment of the requirements for the Ph.D. degree.

Received 5/28/76. Accepted 6/ 1/77.

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