Ribosome assembly in eukaryotes

Fromont‐Racine, Micheline; Senger, Bruno; Saveanu, Cosmin; Fasiolo, Franco

doi:10.1016/s0378-1119(03)00629-2

Cited by 543 publications

(568 citation statements)

References 215 publications

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“…However, the total level of rpL11 was not changed by rpS3 knockdown (Supplementary Figure S2). Next, we checked rRNA processing, as ribosome biogenesis is involved in the sequential processing of pre-rRNA (Fromont-Racine et al, 2003;Granneman and Baserga, 2004). RpS3 knockdown raised a significant diminution of 18S rRNA (Figure 1e, left) and, in particular, an extensive accumulation of 30S and 32S pre-rRNA intermediates (Figure 1e, right).…”

Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 99%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

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Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 99%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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“…Upon transcription in the nucleolus, the pre-rRNA undergoes a series of cleavages and modifications while being assembled into ribosomal preparticles upon hierarchical addition of ribosomal proteins. 1 In yeast, ≈200 assembly factors and several small nucleolar RNAs have been shown to participate to these processes. In higher eukaryotes, though the core components have been conserved, differences were reported [2][3][4][5] suggesting that ribosome biogenesis has become more complex with evolution.…”

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confidence: 99%

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

et al. 2015

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International audienceRibosome biogenesis is an essential cellular process. Its impairment is associated with developmental defects and increased risk of cancer. The in vivo cellular responses to defective ribosome biogenesis and the underlying molecular mechanisms are still incompletely understood. In particular, the consequences of impaired ribosome biogenesis within the intestinal epithelium in mammals have not been investigated so far. Here we adopted a genetic approach to investigate the role of Notchless (NLE), an essential actor of ribosome biogenesis, in the adult mouse intestinal lineage. Nle deficiency led to defects in the synthesis of large ribosomal subunit in crypts cells and resulted in the rapid elimination of intestinal stem cells and progenitors through distinct types of cellular responses, including apoptosis, cell cycle arrest and biased differentiation toward the goblet cell lineage. Similar observations were made using the rRNA transcription inhibitor CX-5461 on intestinal organoids culture. Importantly, we found that p53 activation was responsible for most of the cellular responses observed, including differentiation toward the goblet cell lineage. Moreover, we identify the goblet cell-specific marker Muc2 as a direct transcriptional target of p53. Nle-deficient ISCs and progenitors disappearance persisted in the absence of p53, underlying the existence of p53-independent cellular responses following defective ribosome biogenesis. Our data indicate that NLE is a crucial factor for intestinal homeostasis and provide new insights into how perturbations of ribosome biogenesis impact on cell fate decisions within the intestinal epithelium

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“…26), but downstream of the ribosomal RNA transcription machinery. There are more than 170 ribosome assembly factors 27 and the finding that only a small number of them induce p53 in our screen indicates that p53 monitors specific steps in the assembly process. Interference with their functions propagates signalling through the p53 pathway, explaining the wild-type-specific phenotype.…”

Section: Genome-scale Synthetic Interaction Rnai Screen With Tp53mentioning

confidence: 76%

A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly

et al. 2011

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TP53(tumour protein 53) is one of the most frequently mutated genes in human cancer and its role during cellular transformation has been studied extensively. However, the homeostatic functions of p53 are less well understood. Here, we explore the molecular dependency network of TP53 through an RNAi-mediated synthetic interaction screen employing two HCT116 isogenic cell lines and a genome-scale endoribonuclease-prepared short interfering RNA library. We identify a variety of TP53 synthetic interactions unmasking the complex connections of p53 to cellular physiology and growth control. Molecular dissection of the TP53 synthetic interaction with UNRIP indicates an enhanced dependency of TP53-negative cells on small nucleolar ribonucleoprotein (snoRNP) assembly. This dependency is mediated by the snoRNP chaperone gene NOLC1 (also known as NOPP140 ), which we identify as a physiological p53 target gene. This unanticipated function of TP53 in snoRNP assembly highlights the potential of RNAi-mediated synthetic interaction screens to dissect molecular pathways of tumour suppressor genes.More than 30 years of intense research on the tumour suppressor gene TP53 has revealed its relevance in many aspects of tumour biology (reviewed in ref. 1). It is now well established that p53 (the protein product of TP53) activation leads to the execution of a complex genetic program that limits cellular proliferation and leads to senescence or apoptosis 2,3 . Several lines of evidence have pointed to an under-appreciated homeostasis function of p53 in normal, unstressed cells 4 . As a transcription factor, p53 can mediate the expression levels of its target genes, thereby adjusting cellular homeostasis of basic metabolism 5 , balance of reactive oxygen species 6,7 , stem cell identity and reprogramming 8 and animal reproduction 9 . These data establish an important role for p53 in cellular homeostasis and indicate that p53-loss-of-function cells become genetically rewired in a way that discriminates them from wild-type cells, a premise that could be explored for the identification of possible p53 genetic dependencies.Synthetic interaction screens have led the way in identifying new and unanticipated functional interactions between seemingly unrelated protein complexes in yeast 10,11 . In mammalian cells, RNA interference (RNAi)-based synthetic interaction screens are a promising approach to dissect genetic dependencies and the first studies on mammalian synthetic interactions of oncogenes have demonstrated the power of this approach 12,13 . Furthermore, synthetic lethal screens have identified genes that sensitize cells to different chemical drugs 14,15 . Several synthetic interactions with tumour suppressor genes have also been published 11,16 , but to our knowledge a genome-scale survey for synthetic interactions of a tumour suppressor gene has not been reported. Here, we present the results of a systematic investigation of TP53 genetic dependencies and characterize in molecular detail a homeostatic function of p53 in snoRNP biogen...

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Ribosome assembly in eukaryotes

Cited by 543 publications

References 215 publications

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells

A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly

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