The G₁-S transition is promoted by Rb degradation via the E3 ligase UBR5

Mammalian cells make the decision to divide at the G₁-S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Passage through the G₁-S transition is initially driven by Rb inactivation via phosphorylation and by Rb's decreasing concentration in G₁. While many studies have identified the mechanisms of Rb phosphorylation, the mechanism underlying Rb's decreasing concentration in G₁ was unknown. Here, we found that Rb's concentration decrease in G₁ requires the E3 ubiquitin ligase UBR5. UBR5 knockout cells have increased Rb concentration in early G₁, exhibited a lower G₁-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.