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Induction of DNA Polymerase during Liver Regeneration in Rats on Controlled Feeding Schedules¹

Departments of Physiology and Pharmacology [P. B. D., E. F. B.] and Medicine [J. L.], Duke University Medical Center, Durham, North Carolina 27710

The activity of 2 nonmitochondrial forms of DNA polymerase, designated DNA polymerases and ß, was investigated during liver regeneration in regimented rats. In accord with Barbiroli and Potter, we observed that regimentation of rats with respect to temperature, light and darkness, and availability of food resolves the DNA synthesis response to partial hepatectomy into 2 peaks, one occurring at a fixed time after operation and the other entrained by the environmental conditions. The peaks can be fused or separated depending on the timing of the operation. For this study, operation times were selected to given both patterns of DNA synthesis as measured by the uptake of radioactive thymidine into DNA. For both operation times, DNA polymerase activity in the nuclear extract correlated temporally and qualitatively with radioactive thymidine uptake into DNA. At the times of maximal DNA synthesis and polymerase activity, the DNA polymerase was purified from extracts of isolated nuclei. DNA polymerase represented 70% and DNA polymerase ß represented 30% of the recovered activity from the nuclear extract. This is in agreement with the previous observation in nonregimented rats that DNA polymerase is the major activity in nuclei during liver regeneration. For both operation times, DNA polymerase activity in the postmicrosomal fraction was sedimentable and increased 3 to 4 times above the level observed with this same fraction from normal rat liver. This activity was shown to be due to DNA polymerase only with this subcellular fraction. DNA polymerase activity with this fraction peaked 4 to 6 hr after the time of maximal radioactive thymidine incorporation into DNA. DNA polymerase activity in the microsome fraction did not change significantly after partial hepatectomy. This activity has been shown to represent DNA polymerase ß. Prior administration of cycloheximide and actinomycin abolished the rise in DNA polymerase activity in the nucleus and postmicrosomal fraction. Hydroxyurea did not prevent the rise in DNA polymerase activity with those subcellular fractions but did inhibit over 90% of the uptake of radioactive thymidine into DNA. These data suggest, but do not prove, that DNA polymerase activity is induced in response to the stimulus(i) for liver regeneration.

¹ This investigation was supported by USPHS Grants CA08800, CA11265, and CA15360 from the National Cancer Institute and by the Duke Endowment Fund.

² This work is a part of the thesis submitted to Duke University in 1973 in partial fulfillment of the requirement for the Ph.D. degree. Present address: National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, Bethesda, Md. 20014.

³ Present address: The Worcester Foundation for Experimental Biology, Shrewsbury, Mass. 01545. To whom requests for reprints should be addressed.

Received 8/ 6/75. Accepted 10/24/75.