Cell cycle regulators [HN2] govern key transitions in the life of a cell—when to begin DNA replication and when to enter mitosis and divide. Preeminent among cell cycle regulators is the family of cyclin-dependent kinases (p34 CDK) and their partner cyclins,[HN3] which together form heterodimer protein kinases (1). Reflecting that preeminence, Cdk-cyclin was crowned the cell cycle's “engine”(2): How goes Cdk-cyclin, so goes the cell cycle.

Changes in cell physiology, particularly damage to DNA, stop the cell cycle either before DNA replication in G 1 (termed the G 1 checkpoint) or before mitosis in G 2 [the G 2-M checkpoint (3, 4)]. In many cell types DNA damage response pathways cause arrest by regulation of Cdk-cyclin through checkpoint proteins, which sense damage and transduce an inhibitory signal (3). Until recently it was unclear whether Cdc2,[HN4] a prominent member of this Cdk family and a major mitotic activator in yeast, even plays a role in arrest in G 2 after damage. Nor was it clear how the checkpoint proteins transmit a signal to cause arrest. In the last year, the functions of both Cdc2 and checkpoint proteins have become clearer, and an ever more detailed hypothesis for a checkpoint pathway has emerged, culminating in three reports (pages 1495, 1497, and 1501 1501) in this week's issue from fission yeast, human, and mouse (5–7).