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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Structures and functions of the tumor suppressor p53
1Department of Biology, University of York, UK.
Abstract:
The tumour suppressor p53 plays a crucial role in the cellular response to DNA damage. The p53 protein is able both to detect sites of DNA damage and to interact with DNA in a sequence-specific manner and function in the regulation of target gene expression. These two properties map to discrete functional domains of the protein, the C-terminus and the central core domain respectively. They are essential for integration of a normal cellular response to DNA damage, with initiation of either G1 cell cycle arrest or apoptosis. This review considers the domain structure of p53 in relation to the protein's various functions, together with the importance of tertiary structure and conformational flexibility. The precise regulation of p53 function remains to be established, although the protein is known to be phosphorylated/de-phosphorylated by a number of specific protein kinases/phosphatases. A recent discovery indicates that p53 may be activated by autoproteolysis and that proteolytic cleavage is induced by direct interaction with sites of DNA damage. This process is reminiscent of the bacterial Lex A system and would provide one mechanism for activation of p53 in response to cellular DNA damage.
Insights
The tumor suppressor p53 protein detects DNA damage and regulates gene expression. Its structure and activation by autoproteolysis are key to cellular responses like cell cycle arrest or apoptosis.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The tumor suppressor p53 protein is critical for cellular responses to DNA damage.
- p53 possesses distinct domains for DNA damage detection and sequence-specific DNA interaction.
- These functions are essential for initiating cell cycle arrest or apoptosis.
Purpose of the Study:
- To review the domain structure of p53 in relation to its functions.
- To discuss the importance of tertiary structure and conformational flexibility.
- To explore mechanisms regulating p53 activation, including novel findings on autoproteolysis.
Main Methods:
- Review of existing literature on p53 structure and function.
- Analysis of p53's domain organization and its correlation with cellular activities.
- Discussion of regulatory mechanisms, including phosphorylation and autoproteolysis.
Main Results:
- p53's C-terminus and central core domain are crucial for DNA damage response.
- Tertiary structure and conformational flexibility significantly influence p53 activity.
- p53 activation may involve autoproteolysis, similar to the bacterial Lex A system, upon interaction with DNA damage sites.
Conclusions:
- p53's domain structure dictates its role in DNA damage response pathways.
- Understanding p53's regulation, including novel activation mechanisms, is vital for comprehending cellular integrity.
- The potential autoproteolysis activation pathway offers new insights into p53's function in DNA repair and cell fate decisions.
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