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Guarding the ‘translation apparatus’: defective ribosome biogenesis and the p53 signaling pathway

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Abstract Ribosomes, the molecular factories that carry out protein synthesis, are essential for every living cell. Ribosome biogenesis, the process of ribosome synthesis, is highly complex and energy consuming. Over the last decade, many exciting and novel findings have linked various aspects of ribosome biogenesis to cell growth and cell cycle control. Defects in ribosome biogenesis have also been linked to human diseases. It is now clear that disruption of ribosome biogenesis causes nucleolar stress that triggers a p53 signaling pathway, thus providing cells with a surveillance mechanism for monitoring ribosomal integrity. Although the exact mechanisms of p53 induction in response to nucleolar stress are still unknown, several ribosomal proteins have been identified as key players in this ribosome–p53 signaling pathway. Recent studies of human ribosomal pathologies in a variety of animal models have also highlighted the role of this pathway in the pathophysiology of these diseases. However, it remains to be understood why the effect of ribosomal malfunction is not a universal response in all cell types but is restricted to particular tissues, causing the specific phenotypes seen in ribosomal diseases. A challenge for future studies will be to identify additional players in this signaling pathway and to elucidate the underlying molecular mechanisms that link defective ribosome synthesis to p53. WIREs RNA 2011 2 507–522 DOI: 10.1002/wrna.73 This article is categorized under: Translation > Ribosome Biogenesis Translation > Translation Regulation

The p53 signaling pathway. The tumor suppressor p53 protein plays the central role in coordinating a complex network of signaling pathways that prevent aberrant cell growth and proliferation. In normal conditions, p53 is maintained at low steady‐state levels. Crucial for this regulation are two proteins, murine double minute 2 (MDM2) and MDMX. MDM2, through its E3 ligase function, mediates the attachment of ubiquitin (Ub) molecules to p53 and targets it for proteasomal degradation. MDM2 also binds p53 and influences its transcriptional activity. MDMX lacks the E3 ligase function and suppresses the transcriptional activity of p53, which is independent of MDM2. However, it also forms a heterodimeric complex with MDM2 and stimulates MDM2‐mediated p53 degradation. The expression of MDM2 is controlled by p53 itself through a negative feedback loop (see text for details). MDMX levels are controlled by MDM2 through the Ub‐mediated degradation. Deregulated functions of these p53 inhibitory proteins are critical for an activated p53 response in stress situations. For example, exposures to ionizing radiation, ultraviolet (UV) light, and many other DNA‐damaging stressors activate several kinases [ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and other checkpoint kinases], which modify p53, MDMX, and MDM2. The modifications cause conformational changes in these proteins and block their interactions, resulting in p53 stabilization. Overexpression of oncogenes stimulates the production of alternative reading frame (ARF; p14ARF in human, p19ARF in mouse) that binds to MDM2 and stabilizes p53. An impaired ribosome biogenesis causes the release of several RPs, which bind to and suppress the E3 ligase activity of MDM2, resulting in p53 accumulation. An activated p53 protein subsequently transactivates several target gene expressions. Depending on the cell type and the stressors, the consequence could either be cell cycle arrest, DNA repair, apoptosis, or senescence. Basal levels of p53 (inactivated state) also contribute to many cellular processes in normal cells, which are independent of its gene transcription functions.

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p53‐Dependent surveillance system for monitoring ribosome biogenesis. The synthesis of ribosomes is a complex and energy‐demanding process that involves the coordinated participation of several hundred factors. In normal cells (upper panel), the biogenesis of the ribosome begins with the transcription of ribosomal DNA into pre‐ribosomal RNA (rRNA) precursors by RNA polymerase I in the nucleolus (gray). This pre‐RNA cluster then undergoes a series of modifications and cleavage by several hundred small nucleolar RNAs (snoRNAs) and ribosome‐associated nucleolar proteins [accessory factors, shown as filled green rhombi; synthesized in the cytoplasm (white)] to form rRNA intermediates and finally the mature rRNAs (18S, 5.8S, and 28S). Seventy‐nine ribosomal proteins (RPs, shown as purple circles; produced in the cytoplasm) and 5S rRNA [synthesized in the nucleoplasm (sky blue)] are imported into the nucleolus, where they associate with other rRNAs to form the small (40S) and large (60S) subunits, which are then assembled and exported to the cytoplasm to form the mature ribosome for the initiation of protein synthesis. Under these conditions, p53 is maintained at low levels in the nucleoplasm by murine double minute 2 (MDM2). In ribosomally stressed cells (lower panel), deficiencies of RPs (shown as dotted purple circles) or accessory factors (shown as partially filled green rhombi) cause defects at various stages of rRNA processing, leading to defective 60S and 40S biogenesis, evoking a nucleolar stress response. This results in the translocation of ribosome‐free RPs or accumulated (unutilized) accessory factors to the nucleoplasm, where they bind and inhibit MDM2, leading to the activation and stabilization of p53. Impaired 40S biogenesis can also lead to translational upregulation of 5′‐terminal oligopyrimidine tract (5′ TOP) messenger RNAs (mRNAs), such as RPL11 and possibly other MDM2‐binding RPs, which can enter the nucleoplasm and intercept the MDM2‐mediated p53 degradation. Depending on the cell type, the consequence of the activated p53 response could either be cell cycle arrest or apoptosis.

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