Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesisCyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis
Faithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this change in histone biosynthesis as DNA replication begins. Here, we use single-cell timelapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the Restriction Point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert. Due to size limitations, representative raw images for main text figures have been included with all raw images available upon request.
American Cancer Society
Pew Charitable Trusts
National Cancer Institute