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The MYCmRNA3'-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels

Item Type:Article
Title:The MYCmRNA3'-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels
Creators Name:Dejure, F.R. and Royla, N. and Herold, S. and Kalb, J. and Walz, S. and Ade, C.P. and Mastrobuoni, G. and Vanselow, J.T. and Schlosser, A. and Wolf, E. and Kempa, S. and Eilers, M.
Abstract:Deregulated expression of MYC enhances glutamine utilization and renders cell survival dependent on glutamine, inducing "glutamine addiction". Surprisingly, colon cancer cells that express high levels of MYC due to WNT pathway mutations are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses translation of endogenous MYC via the 3'-UTR of the MYC mRNA, enabling escape from apoptosis. This regulation is mediated by glutamine-dependent changes in adenosine-nucleotide levels. Glutamine deprivation causes a global reduction in promoter association of RNA polymerase II (RNAPII) and slows transcriptional elongation. While activation of MYC restores binding of MYC and RNAPII function on most promoters, restoration of elongation is imperfect and activation of MYC in the absence of glutamine causes stalling of RNAPII on multiple genes, correlating with R-loop formation. Stalling of RNAPII and R-loop formation can cause DNA damage, arguing that the MYC 3'-UTR is critical for maintaining genome stability when ribonucleotide levels are low.
Keywords:3'-UTR, Glutamine, MYC, RNA, Polymerase II
Source:EMBO Journal
Publisher:EMBO Press / Wiley
Page Range:1854-1868
Date:3 July 2017
Official Publication:https://doi.org/10.15252/embj.201796662
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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