Inactivation of the p53 tumor suppressor is essential for oncogenesis. My preliminary data indicate that p53 mutants that retain DNA binding capacities (ie p53 R282W) mediate oncogenesis through distinct transcriptional mechanisms compared to other p53 mutants. p53 R282W binds chromatin at canonical p53 sites, yet does not activate canonical p53 targets. Instead, p53 in R282W-containing cell lines activates gene neighbors of canonical p53 targets, as well as genes that reside in clusters in the genome. Critically, p53 in mutant cells drives expression of the HMGA1, a cancer-associated DNA-bending factor that facilitates chromatin looping. I propose a model in which HMGA1 modifies p53 activity by inducing p53 target-switching and long-range gene activation, and by driving p53 genomic recruitment to AT-rich p53 response elements, which are preferentially bent by HMGA1. I hypothesize that HMGA1 modulates the activity of wild type and mutant p53 through similar mechanisms. However, based on the lower affinity of p53 mutants for DNA, I predict that HMGA1 will have more pronounced effects on genomic recruitment of mutant p53. This work has the potential to transform our understanding of p53 biology by demonstrating a unifying mechanism by which wild type and mutant p53 are hijacked to promote cancer.
Mutations in the p53 tumor suppressor protein are found at high frequencies across many cancer types, and are associated with particularly poor patient prognosis. By testing the model that the DNA-bending protein, HMGA1, redirects mutant and wild type p53 activity to drive transcription of cancer-associated genes rather than tumor suppressor genes, the proposed research has the potential to define a unifying mechanism of oncogenesis in wild type and mutant p53 cancers.
