Mutational Disruption of TP53: A Structural Approach to Understanding Chemoresistance

Area of Science:

• Molecular Biology
• Structural Biology
• Cancer Genomics

Background:

• The tumor suppressor protein p53 is crucial for genomic stability, regulating DNA repair, cell cycle arrest, and apoptosis.
• TP53 gene mutations are common in human cancers, linked to chemoresistance and poor outcomes, particularly when affecting the DNA-binding domain.

Purpose of the Study:

• To systematically map all reported TP53 mutations onto 3D structures of the p53 protein.
• To analyze mutation distribution, structural context, and functional impact on p53 stability and DNA binding.

Main Methods:

• Collected TP53 mutations from the COSMIC database.
• Mapped mutations onto experimentally resolved p53 structures (Protein Data Bank) and AlphaFold models.
• Classified mutations by structural context (core, interface, binding sites, disordered regions).
• Evaluated mutation effects using sequence- and structure-based predictive tools.

Main Results:

• Identified distinct TP53 mutational hotspots and differential distribution across structural regions.
• Demonstrated context-dependent effects of mutations on protein stability and DNA-binding capacity.
• Highlighted a subset of mutations consistently predicted to destabilize p53, suggesting functional inactivation.

Conclusions:

• Provides a comprehensive structural map of TP53 alterations.
• Offers insights into mutation-specific mechanisms of p53 dysfunction.
• Aims to guide precision therapeutic strategies for restoring p53 tumor-suppressive functions.