Activating mutations in BRAF are common in cutaneous melanoma, yet mutational inactivation of the tumor suppressor TP53 is relatively rare despite widespread attenuation of TP53 function, suggesting alternate mechanisms of TP53 inhibition. Using proximity-dependent proteomic mapping, we define a BRAFV600E-specific interactome and identify a selective interaction between oncogenic BRAF and TP53. We demonstrate that BRAFV600E engages the DNA-binding domain of TP53, drives its localization from the nucleus to the cytoplasm, and suppresses TP53 activity. This functional inhibition persists following DNA damage or pharmacologic disruption of TP53 pathways, demonstrating that oncogenic BRAF constrains TP53 activity. These findings establish a protein interaction through which BRAFV600E functionally inactivates TP53 and reveal a mechanism by which melanoma bypasses TP53-mediated tumor suppression without requiring genetic alteration.
O’Toole et al. (Fri,) studied this question.