Oral Presentation 16th Asian Conference on Transcription 2019

MYC and the principles and consequences of global transcription amplification (1195)

David Levens 1
  1. National Cancer Institute Center for Cancer Research, Washington, DC, United States

The role of the MYC oncoprotein in gene regulation is controversial.   MYC has been considered to be either a conventional sequence-specific DNA binding transcription factor acting through E-boxes (CACGTG) at selected, though abundant targets or  a universal amplifier  recruited to promoters both via DNA-binding and interaction with promoter-bound transcription machinery. Transcription amplification is not uniform; highly expressed genes, are better MYC targets than weakly expressed genes until they saturate.  Conserved MYC protein regions Boxes III and IV prevent excessive positive feedback extending the dynamic range of amplification.  As output saturates, the outputs of genes plateau at different levels, potentially distorting the stoichiometric relationships between individual mRNAs. MYC interacts with a large number of transcription and chromatin components to increase expression.  Because high output transcription may become limited by pent up torsional stress, MYC binds and activates topoisomerase enabling them to more efficiently remove impeding supercoils.

 MYC levels must be precisely set to maintain cellular homeostasis and proper responses to stimuli.  High or low setpoints for MYC are epigenetically maintained in different cells governing their responses to stimuli. Among the factors that control MYC transcription, the Far Upstream Element Binding proteins help to confine MYC transcription within narrow bounds, and without them MYC transcription becomes much noisier. The FUBPs monitor MYC expression in real time by binding sequence selectively to a DNA element, FUSE,  that melts in response to dynamic supercoiling generated during transcription. FUBP1 possess topoisomerase activity, a feature that in principle would help to limit its ability transactivate MYC.