P16INK4A drives RB1 degradation by UTP14A-catalyzed K810 ubiquitination

P16^INK4A expression is inversely associated with RB1 expression in cancer cells, and P16^INK4A inhibits CDK4-catalyzed RB1 phosphorylation. How P16^INK4A and RB1 coordinately express and regulate the cell cycle remains to be studied. In the present study, we found that P16^INK4A upregulated the E3 ligase UTP14A, which led to the ubiquitination of RB1 at K810 and RB1 degradation. P16^INK4A loss consistently disrupted the UTP14A-mediated degradation of RB1 and caused RB1 accumulation. Functionally, P16^INK4A 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^INK4A and RB1 expression and that disruption of this loop may partially rescue the biological outcomes of P16^INK4A loss. We also revealed a hitherto unknown function for <i>P16</i> ^<i>INK4A</i> in regulating proteome-scale ubiquitination by inhibiting cell proliferation, which may be useful for the development of anticancer drugs.