Wee1 inhibition decouples Cdk1 and Plk1 activities: a role for gradual Cdk1 activation throughout G2 phase

At completion of DNA replication, the mitotic kinases CDK1 and PLK1 are activated. Their activities increase slowly through early G2 phase, but the reason for this low-level activity before mitotic entry is not clear. Using a combination of experiments and mathematical modelling, we find that gradual CDK1 activation through G2 phase stimulates production of mitotic factors and coordinates activation of CDK1 and PLK1. We find that inhibition of CDK1 during G2 phase limits transcription of mitotic factors.

Conversely, the duration of premature mitosis by forced activation of CDK1 is inversely related to the time-point in G2 when mitosis is triggered. Forced CDK1 activation not only leads to a lack of mitotic factors, but also decouples CDK1 and PLK1 activation. Accordingly, we find that duration of forced mitosis by WEE1 inhibition can be partially rescued by expression of constitutively active PLK1. Our results show a function for slow mitotic kinase activation through G2 phase and suggests a mechanism for how the timing of mitotic entry is linked to preparation for mitosis.

Highlights

• Slow Cdk1 activation through G2 phase coordinates expression of mitotic proteins and activation of mitotic kinases

• The duration of forced mitosis by WEE1 inhibition depends on when in G2 mitosis is triggered

• Forced CDK1 activation decouples CDK1 and PLK1 activation

• The duration of forced mitosis can be partially rescued by expression of constitutively active PLK1