The Role of p53 in Ribosomopathies

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Impaired ribosome biogenesis is the underlying cause of the pathological conditions collectively known as ribosomopathies. Several hypotheses have been advanced to explain the mechanisms by which deficiencies in ribosome biogenesis interfere with developmental processes leading eventually to the emergence of these diseases. In recent years it has become clear that perturbation of this process triggers a cell-cycle checkpoint that, through activation of the tumor-suppressor p53, leads to cell-cycle arrest and apoptosis. Indeed, evidence is accumulating from studies in animal models that the unscheduled activation of p53 is responsible for perturbations in tissue homeostasis that cause the development of ribosomopathies such as Treacher-Collins syndrome (TCS) and 5q- syndrome. These findings imply that inhibition of p53, or better, of mechanisms that specifically lead to p53 activation in response to inhibition of ribosome biogenesis, could be targeted in the treatment of ribosomopathies where activation of p53 is shown to play a pathogenic role.

Section snippets

Ribosome Biogenesis and Cell-Cycle Checkpoints

Since the topic of ribosome biogenesis is treated in great detail elsewhere in this issue, we will give only a limited overview of this process and, instead concentrate on the intimate connections between ribosome biogenesis and cell-cycle progression. Ribosome biogenesis is initiated within a distinct nuclear compartment, the nucleolus, which is organized around sites of rRNA transcription.15 rRNA is transcribed by RNA polymerase I, a dedicated RNA polymerase, into a pre-rRNA precursor that,

The Role of p53

An important question raised by the studies of Volarevic et al is the identity of the cellular components that mediate the effects of the cell-cycle checkpoint linked to ribosome biogenesis. As mentioned above, from studies conducted over the last 10 years p53 has emerged as a major player in the cellular response to perturbations in ribosome biogenesis (Figure 2). The first evidence came from studies of Bop1, a nucleolar protein required for the biogenesis of 60S ribosomes.34 Strezoska and

Mechanism of p53 Activation by Inhibition of Ribosome Biogenesis

As described above, p53 activity and function is regulated at several levels, including protein stability and post-translational modifications (see Kruse and Gu37 for a review). In the case of inhibition of ribosome biogenesis, upregulation of p53 protein stability appears to play a key role. That is, p53 protein is targeted to ubiquitin-mediated degradation by the E3 ubiquitin ligase mouse double mutant 2 (MDM2, HDM2 in humans) such that p53 accumulation requires the inactivation of MDM2.37

Role of p53 in the Pathogenesis of Ribosomopathies

The studies of in vivo models summarized in the section above demonstrate that p53 upregulation triggered by impaired ribosome biogenesis can result in a number of severe pathogenic phenotypes, and suggest that aberrant p53 upregulation may be responsible for the development of ribosomopathies. Recently, evidence has accumulated to support such a model in both TCS and 5q- syndromes. For other diseases, such as Diamond-Blackfan anemia (DBA), the story appears to be more complex and the case for

Conclusions and Perspectives

Understanding the cellular mechanisms that are induced by impaired ribosome biogenesis is crucial for the development of novel therapeutic strategies for the treatment of ribosomopathies. With this knowledge, new therapies could be aimed at reverting the antiproliferative and pro-apoptotic responses that those lesions elicit. The identification of p53 as a central player in cell-cycle checkpoints triggered by inhibition of ribosome biogenesis, and the involvement of these checkpoints in model

Acknowledgments

The authors would like to thank Maryellen Daston for editing the manuscript and Glenn Doerman for help with the figures. S.F. and G.T. are supported by the challenge grant RC1 DK087680 from theNIDDK/NIH.

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