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Molecular Pharmacology, Vol 14, 278-289, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Deoxyribonucleic Acid Synthesis and Replicon Elongation in Mammalian Cells Exposed to Methyl Methanesulfonate

DAN B. DAHLE 1, T. D. GRIFFITHS 1, and J. G. CARPENTER 1

1 Department of Radiation Biology and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

DNA synthesis in Chinese hamster V-79 cells exposed to the alkylating agent methylmethanesulfonate (MMS) was investigated by radioactively labeled thymidine incorporation, followed by Geiger counting, liquid scintillation counting, cell radioautography, and DNA fiber radioautography. Exposure of randomly dividing cells to MMS results in a rapid, dose-dependent decline in the rate of cellular DNA synthesis, followed later by an apparent recovery in the rate of DNA synthesis. The inhibition of DNA synthesis cannot be explained by effects on cell progression or thymidine transport, or by any apparent effects on thymidine metabolism. Analysis of the lengths of labeled segments in DNA fiber radioautograms indicated that MMS significantly decreases either the rate or extent of DNA chain elongation. This inhibition is only temporary, however, since by 6 or 10 hr following treatment with 1 or 3 mM MMS, respectively, the lengths of replication segments return to control values. The degree of inhibition of cellular DNA synthesis following exposure to MMS parallels the inhibition of DNA chain elongation but is quantitatively greater over the entire time course of the experiment. This suggests that exposure to MMS results in constant but protracted inhibition of replicon initiation events. These findings are discussed in terms of the lesions that MMS is known to produce in DNA and their possible relationship to two known mechanisms of inhibition of DNA synthesis.

Note:
ACKNOWLEDGMENTS The authors thank Drs. Chris Lange, Rick McKee, Louise Prakash, and Ken Wheeler for their critical evaluation of this manuscript, and Dr. Fred Sherman for kindly redistilling the MMS.

Submitted on August 25, 1977
Accepted on November 21, 1977




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