Modulation of purine synthesis and phosphoribosyl-pyrophosphate content in human fibroblasts at different population doublings

Abstract

Human diploid fibroblasts of embryonic origin which display the limited lifespan phenomenon, respond to purine base deprivation with a large accumulation of phosphoribosylpyrophosphate when studied at early population doubling levels. This suggests that the purine salvage enzymes are the main consumers of phosphoribosylpyrophosphate in such cells. There is a strong positive correlation between the rate of de novo purine synthesis and the phosphoribosylpyrophosphate content, consistent with its role in the first and rate-limiting reaction of de novo purine synthesis. With increasing population doublings, the cells become less responsive to purine base deprivation; the phosphoribosylpyrophosphate does not increase significantly and a lower rate of de novo purine synthesis is observed. As the rate of cell replication decreases with serial passages, it becomes apparent that such cells appropriately adjust the concentration of phosphoribosylpyrophosphate, thereby controlling the rate of purine synthesis according to their needs for cellular growth.