P16 drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination.

P16 expression is inversely associated with RB1 expression in cancer cells, and P16 inhibits CDK4-catalyzed RB1 phosphorylation. How P16 and RB1 coordinately express and regulate the cell cycle remains to be studied. In the present study, we found that P16 upregulated the E3 ligase UTP14A, which led to the ubiquitination of RB1 at K810 and RB1 degradation. P16 loss consistently disrupted the UTP14A-mediated degradation of RB1 and caused RB1 accumulation. Functionally, P16 loss inhibited RB1 ubiquitination in a cell cycle progression-independent fashion and inhibited proteome-scale ubiquitination in a cell cycle progression-dependent manner. Our findings indicate that there is a negative feedback loop between P16 and RB1 expression and that disruption of this loop may partially rescue the biological outcomes of P16 loss. We also revealed a hitherto unknown function for in regulating proteome-scale ubiquitination by inhibiting cell proliferation, which may be useful for the development of anticancer drugs.