MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain

MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYC’s global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, a subunit shared between several Histone Acetyl-Transferase complexes. The protein-protein binding between MYC and TRRAP predominantly relies on two of the N-terminal negative clusters that are located outside MYC-Box-II (MBII) and drive oncogenesis. Our work identifies a new multivalent MYC subdomain that presents new therapeutic vulnerabilities providing invaluable insights for the development of new therapeutic approaches.