What is it about?

In this paper we offer an explanation to how the tumor suppressor protein p53 orchestrates responses to cellular needs that are appropriate for the stress level in a time-dependent manner. Our findings demonstrate that the flexibility properties of p53 DNA binding sites, are a pivotal factor in early-responsive gene expression during stress, by facilitating p53/DNA interactions belonging to early-responsive genes.

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Why is it important?

p53, aptly named the 'Guardian of Homeostasis', meticulously regulates genes crucial for cancer prevention and routine cell activities. We show that p53 REs' flexibility plays a key role in cell-fate decisions in the p53 circuitry. This flexibility is another layer of code within the DNA double helix, precisely Influencing the timing of p53-dependent gene expression, and thereby contributing to survival versus death decisions in the p53 system.


My scientific research since my PhD days involves various aspects of the sequence-dependence of the DNA double helix and its influence on binding-site recognition by regulatory transcription factors. We have shown in several systems that the structural properties of DNA binding sites play a crucial role in the recognition of DNA by transcriptions factors. This mode of recognition, termed “shape readout” allows several codes to coexist simultaneously on the DNA double helix. In this study we show that functional outcome of p53-dependent gene expression is also coded on the DNA double helix. On the one hand, this will enable us to understand more how this important protein, p53, orchestrates its myriad functional outcomes to combat cellular-stress events. On the other hand, it expands our understanding how the DNA double helix, our central information hub, encodes multiple kinds of information, from coding to genes to packaging and gene regulation, within the sequence of its bases. This discovery opens avenues for designing more effective treatments for conditions where cellular stress plays a critical role, such as in cancer. By manipulating the flexibility of p53 binding sites, we may be able to fine-tune cellular responses and potentially improve the outcomes of stress-related diseases

Prof. Tali E. Haran
Technion - Israel Institute of Technology

Read the Original

This page is a summary of: A molecular mechanism for the “digital” response of p53 to stress, Proceedings of the National Academy of Sciences, November 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2305713120.
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