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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
The role of p53 in ribosomopathies
Stefano Fumagalli1, George Thomas
1Department of Cancer and Cell Biology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237, USA. fumagas@ucmail.uc.edu
Abstract:
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.
Insights
Impaired ribosome biogenesis causes ribosomopathies by activating the tumor suppressor p53, leading to cell cycle arrest. Targeting p53 activation may treat these developmental disorders.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- Ribosomopathies are diseases caused by impaired ribosome biogenesis.
- The exact mechanisms linking ribosome biogenesis defects to disease development are still being investigated.
- Previous hypotheses focused on how these deficiencies interfere with crucial developmental processes.
Purpose of the Study:
- To elucidate the role of cell-cycle checkpoints and p53 activation in ribosomopathies.
- To explore the potential of targeting p53 pathways for therapeutic intervention in specific ribosomopathies.
Main Methods:
- Review of existing hypotheses and accumulating evidence from animal models.
- Analysis of the link between ribosome biogenesis perturbation and p53 activation.
- Investigation of the role of p53 in tissue homeostasis disruption in conditions like Treacher-Collins syndrome and 5q(-) syndrome.
Main Results:
- Defects in ribosome biogenesis trigger a cell-cycle checkpoint.
- This checkpoint leads to the activation of the tumor suppressor p53.
- Activated p53 causes cell-cycle arrest and apoptosis, contributing to tissue homeostasis disruption and disease development.
Conclusions:
- Unscheduled p53 activation is a key mechanism underlying the pathogenesis of certain ribosomopathies.
- Animal model studies support the role of p53 in causing tissue abnormalities seen in Treacher-Collins syndrome and 5q(-) syndrome.
- Inhibiting p53 or its specific activation pathways presents a potential therapeutic strategy for ribosomopathies where p53 plays a pathogenic role.
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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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01:31Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life