Defects in 18 S or 28 S rRNA processing activate the p53 pathway.
The p53 tumor suppressor pathway is activated by defective ribosome synthesis. Ribosomal proteins are released from the nucleolus and block human double minute-2 (Hdm2) that targets p53 for degradation. However, it remained elusive how abrogation of individual rRNA processing pathways contributes to p53 stabilization. Here, we show that selective inhibition of 18 S rRNA processing provokes accumulation of p53 as efficiently as abrogated 28 S rRNA maturation. We describe hUTP18 as a novel mammalian rRNA processing factor that is specifically involved in 18 S rRNA production. hUTP18 was essential for the cleavage of the 5'-external transcribed spacer leader sequence from the primary polymerase I transcript, but was dispensable for rRNA transcription. Because maturation of the 28 S rRNA was unaffected in hUTP18-depleted cells, our results suggest that the integrity of both the 18 S and 28 S rRNA synthesis pathways can be monitored independently by the p53 pathway. Interestingly, accumulation of p53 after hUTP18 knock down required the ribosomal protein L11. Therefore, cells survey the maturation of the small and large ribosomal subunits by separate molecular routes, which may merge in an L11-dependent signaling pathway for p53 stabilization.
Hölzel
Michael
M
Institute of Clinical Molecular Biology and Tumour Genetics, Center of Integrated Protein Science, Munich 85758, Germany. m.holzel@nki.nl
Orban
Mathias
M
Hochstatter
Julia
J
Rohrmoser
Michaela
M
Harasim
Thomas
T
Malamoussi
Anastassia
A
Kremmer
Elisabeth
E
Längst
Gernot
G
Eick
Dirk
D
D002460:Cell Line; D006801:Humans; D009687:Nuclear Proteins; D055550:Protein Stability; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012323:RNA Processing, Post-Transcriptional; D012337:RNA, Ribosomal, 18S / Q000037:antagonists & inhibitors*; D012339:RNA, Ribosomal, 28S / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009687:Nuclear Proteins; D012337:RNA, Ribosomal, 18S; D012339:RNA, Ribosomal, 28S; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D012313:RNA