CELL-CYCLE REGULATION OF THE CYCLIN-A, CDC25C AND CDC2 GENES IS BASEDON A COMMON MECHANISM OF TRANSCRIPTIONAL REPRESSION

The S/G(2)-specific transcription of the human cdc25C gene is due to t he periodic occupation of a repressor element ('cell cycle-dependent e lement'; CDE) located in the region of the basal promoter. Protein bin ding to the major groove of the CDE in G(0) and G(1) results in a phas e-specific repression of activated transcription. We now show that CDE -mediated repression is also the major principle underlying the period ic transcription of the human cyclin A and cdc2 genes. A single point mutation within the CDE results in a 10- to 20-fold deregulation in G( 0) and an almost complete loss of cell cycle regulation of all three g enes. In addition, the cdc25C, cyclin A and cdc2 genes share an identi cal 5 bp region ('cell cycle genes homology region'; CHR) starting at an identical position, six nucleotides 3' to the CDE. Strikingly, muta tion of the CHR region in each of the three promoters produces the sam e phenotype as the mutation of the CDE, i.e, a dramatic deregulation i n G(0). In agreement with these results, in vivo DMS footprinting show ed the periodic occupation of the cyclin A CDE in the major groove, an d of the CHR in the minor groove. Finally, all three genes bear conspi cuous similarities in their upstream activating sequences (UAS). This applies in particular to the presence of NF-Y and Spl binding sites wh ich, in the cdc25C gene, have been shown to be the targets of repressi on through the CDE. Our results strongly suggest that the CDE/CHR-medi ated repression of activation by a specific set of transcription facto rs is a common mechanism of cell cycle-regulated transcription of S/G( 2)-specific genes.