Coupling histone homeostasis to centromere integrity via the ubiquitin-proteasome system

In many eukaryotes, histone gene expression is regulated in a cell cycle-dependent manner, with a spike pattern at S phase. In fission yeast the GATA-type transcription factor Ams2 is required for transcriptional activation of all the core histone genes during S phase and Ams2 protein levels per se show concomitant periodic patterns. We have recently unveiled the molecular mechanisms underlying Ams2 fluctuation during the cell cycle. We have found that Ams2 stability varies during the cell cycle, and that the ubiquitin-proteasome pathway is responsible for Ams2 instability. Intriguingly, Ams2 proteolysis requires Hsk1-a Cdc7 homologue in fission yeast generally called Dbf4-dependent protein kinase (DDK)-and the SCF ubiquitin ligase containing the substrate receptor Pof3 F-box protein. Here, we discuss why histone synthesis has to occur only during S phase. Our results indicate that excess synthesis of core histones outside S phase results in deleterious effects on cell survival. In particular, functions of the centromere, in which the centromere-specific H3 variant CENP-A usually form centromeric nucleosomes, are greatly compromised. This defect is, at least in part, ascribable to abnormal incorporation of canonical histone H3 into these nucleosomes. Finally, we address the significance and potential implications of our work from an evolutionary point of view.