The tumor suppressor p53 plays a central role in mediating the cellular response to DNA damage. p53 is a tetramer containing both structured and intrinsically disordered domains that function synergistically to regulate p53 activity. Using intein technology and NMR spectroscopy, we show that the disordered N-terminal transactivation domain of p53 makes transient intramolecular interactions with the structured DNA-binding domain. These interactions impair binding of p53 to non-specific DNA sequences, but not to p53-specific DNA sequences, providing a mechanism by which p53 can more effectively discriminate between cognate sites and the vastly more abundant non-cognate sites in the genome. Following DNA damage, p53 is activated by phosphorylation at multiple sites. The phosphorylation status of Thr55 controls both activation and termination of p53-mediated transcriptional programs during different stages of the cellular DNA damage response. Thr55 functions as a phosphorylation-dependent regulatory switch that modulates the intramolecular interactions between the disordered transactivation domain and the DNA-binding domain. The strength of these interactions is fine-tuned by the intervening proline-rich domain and is enhanced by Thr55 phosphorylation, resulting in autoinhibition of p53 binding to promoters that regulate cell cycle arrest and apoptosis.

Role of dynamic protein disorder in regulation of DNA binding by the tumor suppressor p53

ACS Spring 2022

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