The MYC mRNA 3′‐UTR couples RNA polymerase II function to glutamine and ribonucleotide levels
| Autor: | Jacqueline Kalb, Guido Mastrobuoni, Nadine Royla, Andreas Schlosser, Stefan Kempa, Elmar Wolf, Susanne Walz, Francesca R Dejure, Carsten P. Ade, Martin Eilers, Jens T. Vanselow, Steffi Herold |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Untranslated region Messenger RNA General Immunology and Microbiology biology DNA damage Three prime untranslated region General Neuroscience Translation (biology) RNA polymerase II Promoter Molecular biology General Biochemistry Genetics and Molecular Biology Glutamine 03 medical and health sciences 030104 developmental biology biology.protein Molecular Biology |
| Zdroj: | The EMBO Journal. 36:1854-1868 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.201796662 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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