Characterization of the BRAF interactome identifies BRAFV600ETP53 interaction in melanoma

Abstract

Melanoma is a highly aggressive and frequently metastatic cancer with its incidence reported to be on the rise. Although most oncogenic drivers in melanoma converge on activation of the RAS>RAF>MEK>ERK MAPK signaling pathway, not all MAPK-activating mutations are recurrently observed in this disease, suggesting a unique functional role for BRAFV600E, which is present in [~]50% of all melanoma cases. However, the prevalence of BRAFV600E alterations over other known MAPK-promoting oncoproteins raises questions regarding whether BRAFV600E possesses additional functions outside of MAPK pathway activation. Thus, we performed TurboID to differentiate the interactome between wild-type BRAF and BRAFV600E. We identified novel interacting partners of normal vs. BRAFV600E, most strikingly being the tumor suppressor TP53. While TP53 is commonly altered or lost across many malignancies, it is notable that TP53 alterations are rare in melanoma. Our studies suggest that BRAFV600E can interact with and inactivate TP53, thus providing potential mechanistic explanation as to why TP53 inactivation or loss is infrequent in BRAFV600E-driven melanoma.