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The Dependence of DNA and RNA Synthesis on Protein Synthesis in Asparaginase-treated Lymphoma Cells

Departments of Pathology and Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107

We studied the effects of asparagine depletion on macromolecular synthesis in an asparagine-dependent line of the 6C3HED lymphoma maintained in suspension culture. Asparagine was removed from the culture by the asparaginase present in guinea pig serum or by deleting it in formulating the medium. Protein, RNA, and DNA synthesis were measured by the incorporation of labeled precursors and the relative rates of synthesis of the individual types of RNA were estimated by a dual-label technique which involves chromatographic fractionation. Guinea pig serum caused a reproducible sequence of inhibitions of macromolecular synthesis. Protein synthesis declined first with biphasic, exponential kinetics. An initial precipitous decline was followed by a more gradual falling off. Accompanying the second phase was an exponential decline in DNA synthesis with a similar half-life. Later RNA synthesis fell in the definite temporal and quantitative sequence of rRNA > DNA-like RNA > tRNA. Both the transcription and the maturation of rRNA were inhibited. Dual-label autoradiorgaphy showed that the inhibition of DNA synthesis was not caused by blocking of the initiation of S-phase but by slowing the rate of DNA synthesis in each cell with a resultant prolongation of S-phase. Omission of asparagine from the medium resulted in a similar sequence of inhibition of macromolecular synthesis but of more gradual onset and progression. Cycloheximide, a specific inhibitor of protein synthesis, rapidly produced a similar sequence of inhibition of nucleic acid synthesis. The effects of asparaginase on nucleic acid synthesis thus seem to be secondary to the inhibition of protein synthesis.

Received 2/ 3/69. Accepted 7/23/69.

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