E242-E261 region of MYC regulates liquid-liquid phase separation and tumor growth by providing negative charges.

MYC is one of the most extensively studied oncogenic proteins and is closely associated with the occurrence and progression of many tumors. Previous studies have shown that MYC regulates cell fate through its liquid-liquid phase separation mechanism, which is dependent on two disordered domains within its N-terminal transcriptional activation regions. In this study, we revealed that the negatively charged conserved region (E242-E261) of the MYC protein controls its condensation formation and irreversible aggregation through multivalent electrostatic interactions. Furthermore, deletion or mutation of the E242-E261 amino acids in the MYC protein enhances the transcriptional function of MYC by altering its aggregation capacity and subsequently promoting cancer cell proliferation. The discovery of the negatively charged region and its regulatory action on the phase separation of MYC provides a new understanding of the aggregation and function of MYC.