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Ordered phosphorylation of cyclin-dependent kinase (CDK) substrates leads to the sequential transcriptional activation and inhibition of hundreds of cell cycle-regulated genes. We find that Ndd1, an activator of genes required for mitotic progression, is both positively and negatively regulated by CDK activity. CDK activity initially stimulates Ndd1-dependent transcription as cells enter mitosis, but prolonged high CDK activity in a mitotic arrest inhibits transcription. The result is a time-delayed negative feedback circuit that generates a pulse of mitotic gene expression. Our results suggest that high CDK activity catalyzes the formation of multiple weak phosphodegrons on Ndd1, leading to its destabilization. Cyclin specificity and phosphorylation kinetics contribute to the timing of Ndd1 destruction. Failure to degrade Ndd1 in a mitotic arrest leads to elevated mitotic gene expression. We conclude that a combination of positive and negative Ndd1 regulation by CDKs governs the timing and magnitude of the mitotic transcriptional program.

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