Gupta Anamika, Bansal Mohit, Ding Jane, Karki Suman, Pandit Madhuparna, Sudarshan Sunil, Ding Han-Fei
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Sci Adv. 2025 Aug 29;11(35):eadv9401. doi: 10.1126/sciadv.adv9401.
The pseudouridine synthase DKC1 regulates internal ribosome entry site (IRES)-dependent translation and is up-regulated in cancers by the MYC family of oncogenes. The functional significance of DKC1 up-regulation and the mechanistic connection between pseudouridylation and IRES-mediated translation remain poorly understood. Here, we report that DKC1 drives an ATF4-mediated transcriptional program that supports amino acid metabolism and stress adaptation. We identify hnRNP A1, an IRES trans-acting factor, as a critical downstream mediator of DKC1 in sustaining ATF4 expression and IRES-dependent translation. Mechanistically, DKC1-mediated pseudouridylation at two specific 28 ribosomal RNA sites is crucial for maintaining hnRNP A1 protein expression. In turn, hnRNP A1 binds and stabilizes ATF4 messenger RNA, preferentially promoting IRES-dependent translation of ATF4 variant 1. Furthermore, cellular stress induces hnRNP A1, which is necessary for stress-induced ATF4 protein expression. Collectively, our findings uncover an MYC-driven DKC1-hnRNP A1 axis that links IRES-dependent translation and ATF4-mediated metabolic adaptation, thereby supporting cancer cell survival under metabolic stress during tumor progression.
假尿苷合酶DKC1调节内部核糖体进入位点（IRES）依赖性翻译，并在癌症中被MYC癌基因家族上调。DKC1上调的功能意义以及假尿苷化与IRES介导的翻译之间的机制联系仍知之甚少。在这里，我们报告DKC1驱动一个由ATF4介导的转录程序，该程序支持氨基酸代谢和应激适应。我们确定IRES反式作用因子hnRNP A1是DKC1在维持ATF4表达和IRES依赖性翻译中的关键下游介质。从机制上讲，DKC1在两个特定的28核糖体RNA位点介导的假尿苷化对于维持hnRNP A1蛋白表达至关重要。反过来，hnRNP A1结合并稳定ATF4信使RNA，优先促进ATF4变体1的IRES依赖性翻译。此外，细胞应激诱导hnRNP A1，这是应激诱导的ATF4蛋白表达所必需的。总之，我们的研究结果揭示了一个由MYC驱动的DKC1-hnRNP A1轴，该轴将IRES依赖性翻译与ATF4介导的代谢适应联系起来，从而在肿瘤进展过程中的代谢应激下支持癌细胞存活。
