5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint
Recently, we demonstrated that RPL5 and RPL11 act in a mutually dependent manner to inhibit Hdm2 and stabilize p53 following impaired ribosome biogenesis. Given that RPL5 and RPL11 form a preribosomal complex with noncoding 5S ribosomal RNA (rRNA) and the three have been implicated in the p53 respon...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-07-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713002829 |
| _version_ | 1818062760574976000 |
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| author | Giulio Donati Suresh Peddigari Carol A. Mercer George Thomas |
| author_facet | Giulio Donati Suresh Peddigari Carol A. Mercer George Thomas |
| author_sort | Giulio Donati |
| collection | DOAJ |
| description | Recently, we demonstrated that RPL5 and RPL11 act in a mutually dependent manner to inhibit Hdm2 and stabilize p53 following impaired ribosome biogenesis. Given that RPL5 and RPL11 form a preribosomal complex with noncoding 5S ribosomal RNA (rRNA) and the three have been implicated in the p53 response, we reasoned they may be part of an Hdm2-inhibitory complex. Here, we show that small interfering RNAs directed against 5S rRNA have no effect on total or nascent levels of the noncoding rRNA, though they prevent the reported Hdm4 inhibition of p53. To achieve efficient inhibition of 5S rRNA synthesis, we targeted TFIIIA, a specific RNA polymerase III cofactor, which, like depletion of either RPL5 or RPL11, did not induce p53. Instead, 5S rRNA acts in a dependent manner with RPL5 and RPL11 to inhibit Hdm2 and stabilize p53. Moreover, depletion of any one of the three components abolished the binding of the other two to Hdm2, explaining their common dependence. Finally, we demonstrate that the RPL5/RPL11/5S rRNA preribosomal complex is redirected from assembly into nascent 60S ribosomes to Hdm2 inhibition as a consequence of impaired ribosome biogenesis. Thus, the activation of the Hdm2-inhibitory complex is not a passive but a regulated event, whose potential role in tumor suppression has been recently noted. |
| first_indexed | 2024-12-10T14:09:20Z |
| format | Article |
| id | doaj.art-283bdd4d6a254f408594748715e41e89 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T14:09:20Z |
| publishDate | 2013-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-283bdd4d6a254f408594748715e41e892022-12-22T01:45:32ZengElsevierCell Reports2211-12472013-07-0141879810.1016/j.celrep.2013.05.0455S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 CheckpointGiulio Donati0Suresh Peddigari1Carol A. Mercer2George Thomas3Laboratory of Cancer Metabolism, ICO/IDIBELL, Hospital Duran i Reynals, Gran Via de l’Hospitalet, 199-08908 Hospitalet de Llobregat, Barcelona, SpainDivision of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Metabolic Diseases Institute, University of Cincinnati Cancer Center, 3125 Eden Avenue, Cincinnati, OH 45267, USADivision of Hematology and Oncology, Department of Internal Medicine, College of Medicine, Metabolic Diseases Institute, University of Cincinnati Cancer Center, 3125 Eden Avenue, Cincinnati, OH 45267, USALaboratory of Cancer Metabolism, ICO/IDIBELL, Hospital Duran i Reynals, Gran Via de l’Hospitalet, 199-08908 Hospitalet de Llobregat, Barcelona, SpainRecently, we demonstrated that RPL5 and RPL11 act in a mutually dependent manner to inhibit Hdm2 and stabilize p53 following impaired ribosome biogenesis. Given that RPL5 and RPL11 form a preribosomal complex with noncoding 5S ribosomal RNA (rRNA) and the three have been implicated in the p53 response, we reasoned they may be part of an Hdm2-inhibitory complex. Here, we show that small interfering RNAs directed against 5S rRNA have no effect on total or nascent levels of the noncoding rRNA, though they prevent the reported Hdm4 inhibition of p53. To achieve efficient inhibition of 5S rRNA synthesis, we targeted TFIIIA, a specific RNA polymerase III cofactor, which, like depletion of either RPL5 or RPL11, did not induce p53. Instead, 5S rRNA acts in a dependent manner with RPL5 and RPL11 to inhibit Hdm2 and stabilize p53. Moreover, depletion of any one of the three components abolished the binding of the other two to Hdm2, explaining their common dependence. Finally, we demonstrate that the RPL5/RPL11/5S rRNA preribosomal complex is redirected from assembly into nascent 60S ribosomes to Hdm2 inhibition as a consequence of impaired ribosome biogenesis. Thus, the activation of the Hdm2-inhibitory complex is not a passive but a regulated event, whose potential role in tumor suppression has been recently noted.http://www.sciencedirect.com/science/article/pii/S2211124713002829 |
| spellingShingle | Giulio Donati Suresh Peddigari Carol A. Mercer George Thomas 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint Cell Reports |
| title | 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint |
| title_full | 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint |
| title_fullStr | 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint |
| title_full_unstemmed | 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint |
| title_short | 5S Ribosomal RNA Is an Essential Component of a Nascent Ribosomal Precursor Complex that Regulates the Hdm2-p53 Checkpoint |
| title_sort | 5s ribosomal rna is an essential component of a nascent ribosomal precursor complex that regulates the hdm2 p53 checkpoint |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713002829 |
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