The G1-specific D- and E-type cyclins are among the most crucial factors controlling cell cycle progression in mammalian cells and are therefore thought to play an important role in tumorigenisis. D-type cyclins have indeed been shown to be endowed with an oncogenic potential. Here, we report that the ectopic expression of human cyclin E, but not cyclin D1, deregulates DNA synthesis in both yeast and mammalian cells. In yeast, induction of DNA synthesis by cyclin E occurs even under conditions of cell cycle arrest in G1 or G2/M, indicating an uncoupling of DNA replication from cell cycle progression. In rat embryo fibroblasts, the cooperative action of Ras and cyclin E induces transformation. These cells, in contrast to those transformed by Ras and cyclin D1, show aberrant levels of DNA synthesis. Since cyclin E is commonly overexpressed in a variety of human tumors, these findings may point to a link between the uncontrolled proliferation and the genomic instability typically seen in malignant tumors. Furthermore they reveal significant differences in the functional properties of cyclin E and D1.