title: Suprainduction of p53 by disruption of 40S and 60S ribosome biogenesis leads to the activation of a novel G2/M checkpoint.
abstract: Impairment of ribosome biogenesis leads to p53 induction and cell cycle arrest, a checkpoint involved in human disease. Induction of p53 is attributed to the binding and inhibition of human double minute 2 (Hdm2) by a subset of ribosomal proteins (RPs): RPS7, RPL5, RPL11, and RPL23. However, we found that only RPL11 or RPL5, in a mutually dependent manner, elicit this response. We show that depletion of RPS7 or RPL23, like depletion of other RPs, except for RPL11 and RPL5, induces a p53 response and that the effects of RPS7 and RPL23 on p53 induction reported earlier may be ascribed to inhibition of global translation. Moreover, we made the surprising observation that codepletion of two essential RPs, one from each subunit, but not the same subunit, leads to suprainduction of p53. This led to the discovery that the previously proposed RPL11-dependent mechanism of p53 induction, thought to be caused by abrogation of 40S biogenesis and continued 60S biogenesis, is still operating, despite abrogation of 60S biogenesis. This response leads to both a G1 block and a novel G2/M block not observed when disrupting either subunit alone. Thus, induction of p53 is mediated by distinct mechanisms, with the data pointing to an essential role for ribosomal subunits beyond translation.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio 45237, USA. stefano.fumagalli@inserm.fr
authors.forename: Stefano
authors.initials: S
authors.lastname: Fumagalli
authors.forename: Vasily V
authors.initials: VV
authors.lastname: Ivanenkov
authors.forename: Teng
authors.initials: T
authors.lastname: Teng
authors.forename: George
authors.initials: G
authors.lastname: Thomas
mesh_terms: D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D006801:Humans; D014176:Protein Biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D054683:Ribosome Subunits, Large, Eukaryotic / Q000235:genetics / Q000378:metabolism*; D054682:Ribosome Subunits, Small, Eukaryotic / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C032493:ribosomal protein L17; C549166:ribosomal protein L5, human