Figure 1.

Eight protein kinases regulate DNA replication in mammalian cells. (A) Mitotic cell cycles produce one and only one copy of the nuclear genome per cell division. Cdk7•CcnH activates Cdk1, Cdk2, Cdk4, and Cdk6. Cdk4•CcnD and Cdk6•CcnD drives cells from a quiescent state (G0) into a proliferative state. Cdk1•CcnB1 triggers mitosis. Cdc7•Dbf4 and Cdk2•CcnE initiate DNA replication. Cdk2•CcnA2 prevents DNA re-replication. Cdk1•CcnA2 prevents premature initiation during G2 phase. Chk1 inhibits Cdk1 and Cdk2 in response to either stalled replication forks or DNA damage. Chk2 inhibits Cdc7 and Cdk2 in response to double strand DNA breaks. (B) If proliferating cells attempt to re-replicate their nuclear DNA before exiting the mitotic cell cycle, the result is a random accumulation of partially re-replicated chromosomes that generates cells with >4C but <8C DNA content that undergo apoptosis. (C) Endocycles produce multiple copies of the nuclear genome in the absence of cell division. In trophoblast giant cells, Cdk2 is essential for DNA replication in the absence of Cdk1 activity, which is inhibited by p57, and Chk1 is selectively suppressed. Cdc7 and Cdk7 are essential for initiation of preIC assembly. Cdk4 and Cdk6 are assumed to be irrelevant.