c-Myc Function

Division Of Basic Sciences - Nci

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Abstract

The c-Myc bHLH-ZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism and differentiation at the cellular, tissue or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc?s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a non-linear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature. Current investigations are exploring the molecular mechanisms exploited by MYC to augment gene expression and to demonstrate how small changes in MYC levels or short pulses of MYC activity may modify the growth of normal and neoplastic cells. The theory that MYC is an amplifier was derived from genome-wide studies of MYC and RNA polymerase binding to chromatin in vivo and RNA expression. We are now testing this theory with an orthogonal set of methods and experiments based on transfections and synthetic biology that thus far fully confirm the predictions of the amplifier model. We are exploring a possible a biochemical mechanism that unifies MYC's diverse activities and that has therapeutic implications. We have recently found that MYC forms a complex with both top1 and top2 simultaneously and stimulates both of their activities in vitro and in vivo. Because DNA topology is an issue for all DNA transactions, via topoisomerases MYC can contribute directly to all genetic processes. We have mapped the sites of binding and activity of this complex (the topoisome) across the genome and have determined that two related complexes form: one includes MYC, TOP1 and TOP2A, while the other includes MYCN, TOP1 and TOP2B. We have found that excessive MYC topoisome activity leads to its replacement by a p53-assembled topoisome that acutely and effectively guards against too much MYC. We have also devised a CRISPR screen to identify the cellular components that contribute to MYC amplifier action and an in vitro transcription system responsive to MYC recruited factors. This screen is designed to be conducted in almost any cell system.