The oncogenic transcription factor c-MYC (MYC) is deregulated and often overexpressed in more than 50% of cancers. MYC deregulation is associated with poor prognosis and aggressive disease, suggesting that the development of therapeutic inhibitors targeting MYC would markedly impact patient outcome. MYC is highly regulated, with a protein and mRNA half-life of ˜ 30 min. The most extensively studied pathway regulating MYC protein stability involves ubiquitylation and proteasomal degradation mediated by the E3-ligase, SCFFbxw7. Here we provide evidence for an SCFFbxw7-independent regulatory mechanism centred on the highly conserved lysine-52 (K52) within MYC Box I. This residue has been shown to be post-translationally modified by both ubiquitylation and SUMOylation, hinting at the interplay of post-translational modifications at this site and the importance of this residue. We demonstrate that mutation of K52 to arginine (R) renders the MYC protein more labile. Mechanistically, we show that the degradation pathway regulated by K52 is independent of the Cullin-RING ligase family of E3-ligases, which includes not only the canonical SCFFbxw7 but also other known MYC-targeting E3-ligases, such as SCFSkp2, SCFβTCRP, SCFFbxo28 and DCXTRUSS. Taken together, our data identify a novel regulatory pathway centred on K52 that may be exploited for the development of anti-MYC therapeutics.