The retinoblastoma tumor suppressor limits ribosomal readthrough during oncogene induced senescence

Abstract

The origin and evolution of cancer cells is considered to be mainly fueled by mutations affecting the DNA sequence. Although errors in translation could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called \"caretakers\" block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretakers genes will prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the retinoblastoma protein (RB) acts as caretaker tumor suppressor by preventing the readthrough of termination codons, a process that allows proteins to be synthetized with additional domains. In particular, we show that expression of oncogenic ras in normal human cells triggers a cellular senescence response characterized by a significant reduction of basal ribosomal readthrough. However, inactivation of the RB tumor suppressor pathway in these cells, using the viral oncoprotein E7 or the oncogenic kinase CDK4 increased readthrough. Conversely, activation of the RB pathway by the tumor suppressor PML, the ribosomal proteins RPS14/uS11 and RPL22/eL22 or the CDK4/6 inhibitor palbociclib reduced readthrough. We thus reveal a novel function for the RB pathway as a caretaker of translational errors with implications for tumor suppression and cancer treatment.