SUMO isopeptidases control p53 independent cell cycle checkpoint

Ribosome biogenesis is a complex and energy demanding process requiring tight coordination with cell growth and proliferation. Impairment of ribosome biogenesis activates a well-defined cell cycle checkpoint that primarily relies on the activation of p53 signalling. However, there is mounting evidence that p53-independent signalling networks connect impaired ribosome biogenesis to cell-cycle checkpoints. So far, however, these pathways have remained largely enigmatic. By characterizing the nucleolar SUMO deconjugases SENP3 and SENP5 we found that both proteases control the SUMOylation state of specific ribosome biogenesis factors and regulate 60S and 40S ribosome maturation pathways. Accordingly, inactivation of SENP3 and SENP5 induces a canonical p53-mediated cell cycle arrest. Intriguingly, however, we discovered that inactivation of SENP3 or SENP5 drastically and specifically downregulates the expression of the key cell cycle regulator CDK6 in a p53-independent process. Accordingly, depletion of SENP3 or SENP5 impairs G1/S transition and cell proliferation in both p53-proficient and p53-deficient cells. Strikingly, we further revealed that impaired ribosome maturation induced by depletion of a panel of ribosome biogenesis factors or by chemical inhibition of RNA polymerase I, generally triggers loss of CDK6 independent of the cellular p53 status. Altogether our data unveil a long-sought p53-independent checkpoint of impaired ribosome biogenesis. Since CDK6 represents a dependency in a subset of cancer entities, we speculate that this checkpoint can serve as an actionable drug target in tumor therapy.