DKC1-mediated pseudouridylation of rRNA targets hnRNP A1 to sustain IRES-dependent translation and ATF4-driven metabolic adaptation.

Abstract

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<i>S</i> 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.