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. Rb is inhibited by two parallel pathways. In the canonical pathway, cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, the Rb concentration decreases during G1 through an unknown mechanism. Here, we found that regulated protein degradation via the E3 ubiquitin ligase UBR5 is responsible for the Rb concentration drop in G1. UBR5 knockout cells have increased Rb concentration in early G1, exhibited a lower G1/S transition rate, and are more sensitive to inhibition of Cdk4/6. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.

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