The 3’-UTR of MYC couples RNA polymerase II function to ribonucleotide levels

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.

MYC基因的异常表达可增强谷氨酰胺利用效率，使细胞存活依赖谷氨酰胺，进而诱导产生“谷氨酰胺成瘾”表型。令人意外的是，因WNT通路突变而高表达MYC的结肠癌细胞，并未呈现谷氨酰胺成瘾表型，反而在谷氨酰胺剥夺时发生可逆的细胞周期阻滞。本研究证实，谷氨酰胺剥夺可通过MYC mRNA的3'非翻译区（3'-UTR）抑制内源性MYC的翻译，使细胞得以逃避凋亡。该调控过程由谷氨酰胺依赖的腺苷核苷酸水平变化所介导。谷氨酰胺剥夺会导致RNA聚合酶II（RNA Polymerase II，RNAPII）在全基因组范围内与启动子的结合减少，并减慢转录延伸进程。尽管MYC激活可恢复大多数启动子区域的MYC结合与RNAPII功能，但延伸过程的修复并不完全；在缺乏谷氨酰胺的情况下激活MYC，会导致RNAPII在多个基因上发生停滞，该现象与R环形成密切相关。RNAPII停滞与R环形成均可引发DNA损伤，这表明MYC的3'非翻译区在核糖核苷酸水平低下时，对维持基因组稳定性至关重要。