Defective macromolecule biosynthesis and cell-cycle progression in a mammalian cell starved for mevalonate

Abstract

The isolation of a somatic cell mutant (Mev-1) with a block in one of the mevalonate-biosynthesizing enzymes (3-hydroxy-3-methylglutaryl-coenzyme A synthase, EC 4.1.3.5) has afforded us the opportunity to test and to extend the hypothesis that a product of mevalonate biosynthesis other than cholesterol is required for cellular proliferation. We present evidence here that both DNA synthesis and protein synthesis are inhibited in this mutant by mevalonate starvation, although RNA synthesis appears to be unaffected. The loss of DNA synthesis and the loss of protein synthesis in this mutant appear to be due to independent processes. DNA synthesis is reversibly inhibited by mevalonate starvation at a unique point in the cell cycle. Resumption of DNA synthesis after readdition of mevalonate exhibits a long lag; the peak of S-phase DNA synthesis occurs approximately 17 hr after mevalonate readdition, suggesting that mevalonate starvation puts cells into a quiescent (G0) state owing to their failure to transit a restriction point. The loss of DNA biosynthesis in the Mev-1 cell is well correlated with the rate of turnover of mevalonate label of certain terpenylated polypeptides.