Pseudouridylation is a common RNA modification that is catalyzed by the family of pseudouridine synthases (PUS). Pseudouridylation can increase RNA stability and rigidity, thereby impacting RNA splicing, processing, and translation. Given that RNA metabolism is frequently altered in cancer, pseudouridylation may be a functionally important process in tumor biology. Here, we showed that the MYC family of oncoproteins transcriptionally upregulates PUS7 expression during cancer development. PUS7 was essential for the growth and survival of MYC-driven cancer cells and xenografts by promoting adaptive stress responses and amino acid biosynthesis and import. ATF4, a master regulator of stress responses and cellular metabolism, was identified as a key downstream mediator of PUS7 functional activity. Induction of ATF4 by MYC oncoproteins and cellular stress required PUS7, and ATF4 overexpression overcame the growth inhibition caused by PUS7 deficiency. Mechanistically, PUS7 induced pseudouridylation of MCTS1 mRNA, which enhanced its translation. MCTS1, a noncanonical translation initiation factor, drove stress-induced ATF4 protein expression. A PUS7 consensus pseudouridylation site in the 3’ untranslated region of ATF4 mRNA was crucial for the induction of ATF4 by cellular stress. These findings unveil a MYC-activated mRNA pseudouridylation program that mitigates cellular stress induced by MYC stimulation of proliferation and biomass production, suggesting that targeting PUS7 could be therapeutic strategy selectively against MYC-driven cancers.

中文翻译：

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MYC 驱动 mRNA 假尿苷化以减轻癌症发展过程中增殖诱导的细胞应激


假尿苷化是一种常见的 RNA 修饰，由假尿苷合酶 （PUS） 家族催化。假尿苷化可以提高 RNA 的稳定性和刚性，从而影响 RNA 的剪接、加工和翻译。鉴于癌症中 RNA 代谢经常发生改变，假尿苷化可能是肿瘤生物学中一个功能上重要的过程。在这里，我们表明癌蛋白的 MYC 家族在癌症发展过程中转录上调 PUS7 表达。PUS7 通过促进适应性应激反应和氨基酸生物合成和输入，对 MYC 驱动的癌细胞和异种移植物的生长和存活至关重要。ATF4 是应激反应和细胞代谢的主要调节因子，被确定为 PUS7 功能活性的关键下游介质。MYC 癌蛋白和细胞应激诱导 ATF4 需要 PUS7，而 ATF4 过表达克服了 PUS7 缺陷引起的生长抑制。从机制上讲，PUS7 诱导 MCTS1 mRNA 的假尿苷化，从而增强其翻译。MCTS1 是一种非经典翻译起始因子，驱动应激诱导的 ATF4 蛋白表达。ATF4 mRNA 3' 非翻译区的 PUS7 共有假尿苷化位点对于细胞应激诱导 ATF4 至关重要。这些发现揭示了一种 MYC 激活的 mRNA 假尿苷化程序，该程序减轻了 MYC 刺激增殖和生物量产生诱导的细胞应激，表明靶向 PUS7 可能是选择性针对 MYC 驱动的癌症的治疗策略。