Figure 9. Proposed model to explain how histone-stress impacts mitosis.

Histone dimers are depicted as small rectangles (H3-H4 in white, H2A-H2B in grey and H2A.Z-H2B in blue). During an unperturbed cell cycle (a, upper scheme), canonical histones and Swe1^WEE1 increase during replication. Swe1^WEE1 will phosphorylate Cdc28^CDK1 and maintain it inactive. During G2, histone synthesis will be repressed and all histones (mRNAs and proteins) that are not incorporated to chromatin as well as Swe1^WEE1 will be degraded. During mitosis, Htz1^H2A.Z will stabilise condensin recruitment at pericentromeric regions allowing the proper function of this complex in chromosome segregation. When histone degradation is compromised (b, lower scheme), cells reach G2 with high levels of histones (histone-stress). This accumulation of histones will promote Cdc28^CDK1 phosphorylation and inactivation. This inhibition will delay the entry into mitosis and presumably give time to the cell to lower histone levels. Since this phosphorylation depends on Swe1^WEE1, we propose that histone-stress promotes Cdc28^CDK1 phosphorylation through a stabilisation of Swe1^WEE1. Cells unable to efficiently lower histone levels after replication will increase the amount of canonical nucleosomes incorporated at centromeres and pericentromeres. We propose that this increase in nucleosome density will decrease the efficient exchange of histone H2A by histone Htz1^H2A.Z, and reduce Htz1^H2A.Z incorporation. This defect in incorporation would consequently lead to a less stable association of condensin to pericentromeres and trigger chromosome segregation defects.