The relationship between 3-hydroxy-3-methylglutaryl (HMG) CoA hibitor compactin, the normal S-phase burst of DNA synthesis was specifically and totally prevented. Finally, the compactin-induced inhibition of DNA synthesis could be completely reversed within minutes by the addition of mevalonate, the product of the HMG CoA reductase reaction. By contrast, addition of cholesterol-rich lipoproteins had no effect upon DNA synthesis in compactin-treated cells. These data demonstrate that HMG CoA reductase activity, and therefore the production of mevalonate, plays an essential role in the synthesis of DNA specifically during the S phase of the cell cycle. Moreover, the results indicate that this function of mevalonate in regulating DNA replication is independent of its conversion to cholesterol.

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