Cdc6: a trifunctional AAA+ ATPase that plays a central role in controlling the G1-S transition and cell survival

Cdc6 is the AAA+ ATPase that assembles prereplicative complexes on replication origins in eukaryotic chromosomes. Recently, the same Cdc6 protein was found to exert two more functions in mammalian cells to promote cell proliferation and survival: ATP-dependent activation of p21(CIP1)- or p27(KIP1)-bound Cdk2-cyclin A/E complexes and obstruction of apoptosome assembly and consequent cell death by forming stable complexes with activated Apaf-1 molecules. These findings not only redefined the biological role of mammalian Cdc6 but also led the discovery of entirely new mechanisms controlling Cdk2 activity and apoptosis. This review focuses on this multi-functional AAA+ ATPase and the newly discovered mechanisms by which it controls the G(1)-S transition and cell survival during proliferation.