The G-S transition is promoted by Rb degradation via the E3 ligase UBR5.

Mammalian cells make the decision to divide at the G-S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Passage through the G-S transition is initially driven by Rb inactivation via phosphorylation and by Rb's decreasing concentration in G. While many studies have identified the mechanisms of Rb phosphorylation, the mechanism underlying Rb's decreasing concentration in G was unknown. Here, we found that Rb's concentration decrease in G requires the E3 ubiquitin ligase UBR5. knockout cells have increased Rb concentration in early G, exhibited a lower G-S transition rate, and are more sensitive to inhibition of cyclin-dependent kinase 4/6 (Cdk4/6). This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.