Chromatin dysregulation by mutant p53

The TP53 gene, which encodes a DNA sequence-dependent transcriptional regulator, is arguably the most frequently mutated gene in human cancer. Whereas wild-type p53 is restricted to its cognate DNA binding sites, mutant p53 (via mutation in the DNA binding domain) is no longer constrained to specific genomic sites. Mutant p53 proteins therefore cannot effectively mediate wild-type p53 tumor suppressive transcriptional programs, thereby enabling permissive tumor growth. Nevertheless, missense mutant forms of p53 can promiscuously alter the transcriptome of the cells they inhabit through association with transcription factors and other chromatin regulators. A global mechanism that could explain mutant p53- dependent gene expression changes would be a useful step in elucidating mutant p53 gain of oncogenic function.