c-Myc Function

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The c-Myc bHLH-ZIP protein is involved in almost all in physiological and pathological processes. When properly functioning MYC controls growth, proliferation, apoptosis, metabolism and differentiation at the cellular, tissue or organismal levels via regulation of numerous target genes. When improperly functioning,by misregulating these targets and these processes MYC contributes to almost all cancers. We have been conducting studies that show that MYC does not act via a defined pathway of oncogenesis, but rather amplifies the flux through virtually all cancer pathways and distrupts homeostatic balance. MYC acts as an amplifier at all rate-determining steps of the transcription cycle, and controls chromatin conformation and DNA topology, that latter through a novel complex of topoisoemrase1 and topoisomerase 2a (similarly, M-MYC forms a comlex wit topoisomerase 1 and topoisomerase 2B). These complexes termed "topoisomes" remove physical impediments that accumulate in the DNA fiber, especially of long genes, to facilitate transcription and replication. Current investigations are exploring the MYC stimulates early steps in the transcription cycle as part of a phase-separated, transcriptionally-active, biomolecular condensate. We are using biochemical and genetic methods to interrogate the machinery that conducts transcription amplification and to distinguish that machinery from the process of transcription activation. Our CRISPR screen has supports the concept that MYC acts throughout the transcription-cycle to accelerate gene output. Some surprises have been found. contrary to expectation, BRD1 is more important for transcriptional amplification than is BRD4. The proteasome may also contribute to the process. Amplifier activity is more heavily dependent on Mediator than is transcription activation. Transcription amplification also requires OGT activity. More evidence suggests that high-output transcription sponsored by MYC is associated with DNA-damage. Some of the damage results from activation of the topoisome, which is necessary to mitigate even greater damage that results from R-loops, transcription-replication conflicts, and replication stress. We are currently conducting collaborative studies with the O'Reilly group (CCR) to understand the detailed mechanism of the assembly and activation of topoisomerase 1 and 2 by MYC and/or p53. In collaboration with Hans Maric at the University of Würzburg we are mapping the determninants of MYC interaction with TOP1, TOP2A, and TOP2B. Knowledge of the precise molecular determinants of these interactions will instruct future experiments to develop pharmacological and biological interventions to interrupt MYC action therapeutically.