Mutant p53 binds RNA to drive mitochondrial dysfunction.

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Tumor suppressor protein 53 (p53) is crucial for genomic stability.
• p53 is frequently deregulated in cancers, often via mutations leading to loss of function.
• Some p53 mutants exhibit gain-of-function properties in cancer.

Purpose of the Study:

• To investigate novel interactions of p53 mutants.
• To understand the loss and gain of function roles of hotspot p53 mutants.
• To explore the mechanisms behind p53 mutant phenotypes.

Main Methods:

• Intein-based μMap photoproximity labeling of p53.
• Characterization of 5 hotspot p53 mutants.
• Cross-linking immunoprecipitation (CLIP) experiments.
• Analysis of RNA binding and downstream effects.

Main Results:

• G245S and R273H p53 mutants bind RNA via their C-terminal domain.
• A conserved RNA binding motif in mutant p53 is enriched in 3'UTRs.
• Mutant p53 binding to RNA promotes ribosomal localization and mitochondrial protein labeling.
• Mutant p53 RNA binding ability alters miRNA processing and causes mitochondrial dysfunction.

Conclusions:

• Mutant p53 gains novel RNA-binding functions contributing to cancer.
• RNA binding by mutant p53 provides mechanistic insight into its gain-of-function phenotypes.
• These findings highlight a new therapeutic target for p53-mutated cancers.