Almost all human tumors express significantly higher levels of MYC protein compared to normal tissues. Mouse models have further demonstrated a direct link between MYC activity and tumorigenesis. Despite its critical role as an oncogene, MYC was long considered an unsuitable therapeutic target, as it is also indispensable for the function of normal cells. Motivated by the question of whether and how the oncogenic role of MYC differs from its physiological function, we have in recent years investigated the mechanisms of MYC-mediated gene regulation in depth, yielding two key insights.

First, we demonstrated that MYC binds to the promoters of all expressed genes and can regulate them (Walz et al., Nature, 2014). However, target genes differ markedly in their affinity for MYC (Lorenzin et al., eLife, 2016). High-affinity targets are regulated even at low MYC concentrations, as found in normal cells, and are essential for cell growth and proliferation. At the very high concentrations present in tumor cells, MYC additionally binds to low-affinity promoters, thereby activating genes that drive tumor-specific processes.

Second, our data support the unexpected model that MYC does not primarily regulate initiation - that is, the transcription rate - but rather loads RNA polymerase II with elongation factors. In the absence of this loading mechanism, RNA polymerase loses much of its processivity (Baluapuri et al., Molecular Cell, 2019; Vogt et al., Gut, 2024). Moreover, MYC also exerts transcription-independent functions, such as preventing DNA damage through its multimerization (Solvie et al., Nature, 2022).