NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription

In eukaryotic cells, histone gene expression is one of the major events tha t mark entry into S phase. While this process is tightly linked to cell cyc le position, how it is regulated by the cell cycle machinery is not known. Here we show that NPAT, a substrate of the cyclin E-Cdk2 complex, is associ ated with human replication-dependent histone gene clusters on both chromos omes 1 and 6 in S phase. We demonstrate that NPAT activates histone gene tr anscription and that this activation is dependent on the promoter elements (SSCSs) previously proposed to mediate cell cycle-dependent transcription. Cyclin E is also associated with the histone gene loci, and cyclin E-Cdk2 s timulates the NPAT-mediated activation of histone gene transcription. Thus, our results both show that NPAT is involved in a key S phase event and pro vide a link between the cell cycle machinery and activation of histone gene transcription.