Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type

Area of Science:

• Molecular Biology
• Cancer Research
• Genomics

Background:

• The tumor suppressor protein p53 plays a critical role in cellular response to stress, including DNA damage.
• Mutations in p53 are common in cancer, and Mdm2 is a key regulator of p53 stability and function.
• The interplay between mutant p53, Mdm2, and wild type p53 in gene regulation remains incompletely understood.

Purpose of the Study:

• To investigate the direct effects of mutant p53 and Mdm2 on wild type p53's gene occupancy and expression.
• To understand the functional consequences of these interactions in the context of radiation response.

Main Methods:

• Integrated RNA-sequencing (RNA-seq) and Chromatin immunoprecipitation sequencing (ChIP-seq) analysis.
• In vivo experiments using isogenically matched mouse strains.
• Utilized radiation response as a biological endpoint.

Main Results:

• Mutant p53 and Mdm2 inhibit only a subset of wild type p53-mediated gene expression.
• Contrary to dominant-negative models, mutant p53 or Mdm2 enhance wild type p53 occupancy on many canonical target genes.
• The C-terminal 19 amino acids of wild type p53 are crucial for suppressing the p53 response, enabling survival at sublethal radiation doses.
• A specific p53 mutant (172H) utilizes non-canonical mechanisms, shared with wild type p53, to regulate gene expression.
• Heterozygous 172H/+ mice exhibit an expanded transcriptome compared to wild type p53+/+ mice.

Conclusions:

• The interaction between mutant p53/Mdm2 and wild type p53 is complex, involving enhanced target gene occupancy rather than solely dominant-negative inhibition.
• Wild type p53's C-terminus plays a regulatory role in survival responses to radiation.
• p53 mutants can engage shared regulatory pathways with wild type p53, leading to altered transcriptional profiles.