DNA damage-dependent cyclin D1 proteolysis: GSK3beta holds the smoking gun.

Ubiquitin mediated degradation of cyclin D1 following the G(1)/S transition counters its mitogen-dependent accumulation during G(1) phase of the cell cycle. Although the cellular machinery responsible for this process has been identified, how this regulatory pathway interfaces with cellular stress responses, often referred to as checkpoints, remains to be established. One intensely investigated checkpoint is the cellular response to DNA damage. When DNA damage is sensed, the corresponding DNA damage checkpoint triggers the inhibition of CDK-dependent cell cycle progression, with arrest coordinated by induction of CDK inhibitors and rapid degradation of specific cyclins, such as cyclin D1. In recent work, we identified a phosphorylation- and Fbx4-dependent cyclin D1 degradation mechanism in response to genotoxic stress.(18) This work revealed that loss of cyclin D1 regulation compromises the intra-S-phase response to DNA damage, promoting genomic instability and sensitization of cells to S-phase chemotherapy, highlighting a potential therapeutic strategy for cancers exhibiting cyclin D1 accumulation.