Role of HUWE1-mediated degradation of MIZ-1 in transcriptional elongation
The MYC family of proteins comprises three transcription factors that drive the genesis of virtually all human tumors. In tumor cells, MYC proteins bind universally to all active promoters. Surprisingly, however, they regulate only a small subset of genes to which they bind and the changes in gene expression in response to alterations in MYC levels are typically small. The discrepancy between universal binding of MYC to active promoters and the weak and selective effects on gene regulation led us to postulate that MYC proteins have critical oncogenic effects that are unrelated to their effects on gene expression. We discovered in the first funding period that MYC promotes double-strand repair at active promoters (Endres, Molecular Cell 2021). Intriguingly, this newly discovered repair function of MYC depends on the ubiquitylation of MYC by a HECT domain ligase, HUWE1, and the project now aims to understand why this is the case.