Multimerization of MYC proteins as oncogenic principle

• Applicant: Professor Dr. Martin Eilers
• Subject Area: Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521472328

The three MYC family oncoproteins are central drivers of human tumorigenesis. Tumors driven by many oncogenes are dependent on elevated MYC expression throughout their lifespan, suggesting that targeting MYC function has high therapeutic potential. This proposal addresses the central question of what biochemical and biophysical mechanisms underlie this dependence. MYC proteins exhibit many features of activating transcription factors and are traditionally considered oncogenic because they maintain the characteristic gene expression patterns of tumor cells. However, despite decades of intensive work, the identity of critical MYC target genes remains unclear. Indeed, many recent discoveries have revealed biochemical features of MYC proteins that are at odds with this model and argue that they have oncogenic functions independent of gene expression. My laboratory has identified two such processes: MYC proteins promote transcription-dependent double-strand break repair at promoters and they resolve transcription-replication conflicts. We have also shown that targeting these processes has high therapeutic potential. MYC proteins resolve TRCs by terminating transcription near promoters when a replication fork approaches. This is surprising because, as mentioned above, they can function as classical activating proteins. A number of previous observations had already indicated that MYC proteins can exist in two states, an activating and a repressive state. Moreover, continuous proteasomal turnover of MYC is required for its activating functions, suggesting that MYC proteins accumulate in a repressive state when turnover is blocked. We have now found that the transition between the two states corresponds to a multimerization and phase transition of MYC proteins. When MYC turnover is blocked or cells are subjected to transcriptional stress, MYC proteins accumulate in multimeric spherical structures and localize to new sites on chromatin. Strikingly, these sites are located near stalled replication forks, and the spherical structures surround the stalled forks. The blockage of sphere formation resulted in double-strand breaks induced by replication stress. This suggests that MYC spheres physically shield blocked replication forks from RNA polymerase. We propose that such spheres exert an important protective function for replication forks under stress conditions and that the ability to multimerize is central to the pervasive oncogenic functions of MYC. This application aims to understand the mechanisms underlying MYC multimerization and to develop tools that allow us to decide whether multimerization and phase transition are indeed central for the oncogenic functions of MYC.

• DFG Programme: Research Grants