The MYC mRNA 3′‐UTR couples RNA polymerase II function to glutamine and ribonucleotide levels

Abstract

Deregulated expression of enhances glutamine utilization and renders cell survival dependent on glutamine, inducing "glutamine addiction". Surprisingly, colon cancer cells that express high levels of 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 via the 3'-UTR of the 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 3'-UTR is critical for maintaining genome stability when ribonucleotide levels are low.

A central role of glutamine in Chlamydia infection

“…It has been shown recently that c-Myc can function in a glutamine sensing pathway since depletion of glutamine causes the rapid depletion of c-Myc via a mechanism dependent on the 3’ UTR of the gene 21 . To rule out that Gln depletion affects Chlamydia growth indirectly via c-Myc downregulation, we used HCT116 cells expressing the MYC-ER fusion protein from a construct lacking the 3’UTR, which allows the restoration of c-Myc expression in Gln-deprived cells.…”

MYC and tumor metabolism: chicken and egg

“…• Deregulated MYC can cause transcriptional elongation in the absence of sufficient nucleotides and induce stalling of RNA polymerases and R-loop formation (Dejure et al, 2017).…”

“… Enhanced expression of MYC causes a decrease in cellular ATP levels and activates AMP‐activated kinase (AMPK) (Liu et al , ; von Eyss et al , ). MYC‐induced metabolic stress can sensitize cells toward apoptosis, in part since AMPK phosphorylates p53 and activates its mitochondrial pro‐apoptotic functions (Nieminen et al , , ). Deregulated MYC can cause transcriptional elongation in the absence of sufficient nucleotides and induce stalling of RNA polymerases and R‐loop formation (Dejure et al , ). Deregulated MYC can cause a catastrophic metabolic imbalance. MYC is part of extended network of helix‐loop‐helix transcription factors and its effects on metabolism are counterbalances by a nutrient‐sensing member of the network, MondoA.…”

MYCN-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

“…Of note, c-MYC regulates glutamine metabolism, at least in part, by repressing miR-23a and miR-23b resulting in enhanced expression of their target gene, glutaminase 18 . Recent reports pointed to a possible feedback mechanism, as MYC translation itself is regulated by intracellular levels of glutamine-derived adenosine nucleotides via a sequence element in the 3´-UTR of the MYC mRNA 6 . In our model cell lines, this effect cannot be analyzed in the absence of endogenous regulator elements in the 3´UTR of the MYCN encoding vectors.…”

“…Deregulated MYC activity comes along with enhanced metabolic stress and increased sensitivity towards apoptosis due to a dependency on continuous supply with nutrients. Glutamine has been identified as a limiting factor for c-MYC dependent cell growth and glutamine deprivation was preferentially inducing apoptosis in MYC-high cells 6 . In neuroblastoma, the most common solid tumor of childhood, elevated MYCN levels are often found due to amplification of the coding gene, N-Myc, which is correlated with poor overall survival of affected patients.…”