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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Rotational positioning of nucleosomes facilitates selective binding of p53 to response elements associated with cell
1Thomas H. Gosnell School of Life Sciences, Rochester Institute of Technology, 85 Lomb Memorial Drive Rochester, NY 14623, USA and Laboratory of Cell Biology, National Cancer Institute, NIH Bg. 37, Room 3035A, Convent Dr., Bethesda, MD 20892, USA.
Abstract:
The tumor suppressor protein p53 exhibits high affinity to the response elements regulating cell cycle arrest genes (CCA-sites), but relatively low affinity to the sites associated with apoptosis (Apo-sites). This in vivo tendency cannot be explained solely by the p53-DNA binding constants measured in vitro. Since p53 can bind nucleosomal DNA, we sought to understand if the two groups of p53 sites differ in their accessibility when embedded in nucleosomes. To this aim, we analyzed the sequence-dependent bending anisotropy of human genomic DNA containing p53 sites. For the 20 CCA-sites, we calculated rotational positioning patterns predicting that most of the sites are exposed on the nucleosomal surface. This is consistent with experimentally observed positioning of human nucleosomes. Remarkably, the sequence-dependent DNA anisotropy of both the p53 sites and flanking DNA work in concert producing strong positioning signals. By contrast, both the predicted and observed rotational settings of the 38 Apo-sites in nucleosomes suggest that many of these sites are buried inside, thus preventing immediate p53 recognition and delaying gene induction. The distinct chromatin organization of the CCA response elements appears to be one of the key factors facilitating p53-DNA binding and subsequent activation of genes associated with cell cycle arrest.
Insights
The tumor suppressor protein p53 binds cell cycle arrest sites more effectively than apoptosis sites in vivo. This difference is due to nucleosome structure, which exposes arrest sites while burying apoptosis sites, influencing gene activation.
Area of Science:
- Molecular Biology
- Genomics
- Epigenetics
Background:
- The tumor suppressor protein p53 has varying affinities for DNA response elements in vivo.
- In vitro binding affinities do not fully explain p53's differential in vivo binding to cell cycle arrest (CCA) sites versus apoptosis (Apo) sites.
- p53's interaction with nucleosomal DNA is a key factor to consider for understanding its in vivo binding preferences.
Purpose of the Study:
- To investigate whether the accessibility of p53 binding sites within nucleosomes differs between CCA-sites and Apo-sites.
- To elucidate the role of chromatin organization in regulating p53's target gene activation.
Main Methods:
- Analysis of sequence-dependent bending anisotropy of human genomic DNA containing p53 sites.
- Calculation of rotational positioning patterns for p53 sites within nucleosomes.
- Comparison of predicted nucleosomal DNA positioning with experimentally observed data.
Main Results:
- CCA-sites are predominantly exposed on the nucleosomal surface, facilitated by DNA sequence-dependent positioning.
- Apo-sites are often predicted and observed to be buried within nucleosomes.
- Distinct chromatin organization of CCA-sites promotes p53 binding and subsequent cell cycle arrest gene activation.
Conclusions:
- Nucleosomal organization significantly influences the accessibility of p53 binding sites.
- The differential chromatin positioning of CCA-sites and Apo-sites is a critical factor in regulating p53's function in vivo.
- This mechanism explains how p53 preferentially activates cell cycle arrest genes over apoptosis genes.
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