期刊
EMBO JOURNAL
卷 36, 期 13, 页码 1854-1868出版社
WILEY
DOI: 10.15252/embj.201796662
关键词
3 '-UTR; glutamine; MYC; RNA polymerase II
资金
- German Research Council [DFG 222/12-1, WO 2108/1-1]
- German Research Council via Graduate School of Life Sciences
- German Research Council via Berlin School of Integrative Oncology
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.
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