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Cell-based studies showed that several Mdm2-binding ribosomal proteins, upon overexpression, stabilize and activate p53. In contrast, here we show in a mouse knockout study that Mdm2-binding ribosomal protein S27-like (Rps27l), upon disruption, activates p53. Germline inactivation of  Rps27l  triggers ribosomal stress to stabilize Mdm2, which degrades Mdm4 to reduce Mdm2-Mdm4 E3 ligase towards p53, leading to p53-dependent apoptotic depletion of hematopoietic stem cells and postnatal death, which is rescued by  Trp53  deletion. Paradoxically, while increased p53 is expected to inhibit tumorigenesis,  Rps27l   −/−   ;Trp53   +/−   mice develop lymphomas at higher incidence with p53 loss-of-heterozygosity and severe genome aneuploidy, suggesting that  Rps27l  disruption impose a selection pressure against p53. Thus, Rps27l has dual functions in p53 regulation: under  Trp53   +/+   background,  Rps27l  disruption triggers ribosomal stress to induce p53 and apoptosis, whereas under  Trp53   +/−   background,  Rps27l  disruption triggers genomic instability and  Trp53  deletion to promote tumorigenesis. Our study provides a new paradigm of p53 regulation.

Ribosomal protein S27-like is a physiological regulator of p53 that suppresses genomic instability and tumorigenesis