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

TLDR

Histone gene expression marks entry into S phase, yet how the cell cycle machinery regulates this process remains unknown. We show that NPAT, a cyclin E–Cdk2 substrate, binds replication‑dependent histone gene clusters, activates transcription via SSCS promoter elements, and that cyclin E–Cdk2 stimulates this NPAT‑mediated activation, linking the cell cycle machinery to histone gene transcription.

Abstract

In eukaryotic cells, histone gene expression is one of the major events that mark entry into S phase. While this process is tightly linked to cell cycle 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 associated with human replication-dependent histone gene clusters on both chromosomes 1 and 6 in S phase. We demonstrate that NPAT activates histone gene transcription 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 stimulates the NPAT-mediated activation of histone gene transcription. Thus, our results both show that NPAT is involved in a key S phase event and provide a link between the cell cycle machinery and activation of histone gene transcription.