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 28S ribosomal RNA sites is crucial for maintaining hnRNP A1 protein expression. In turn, hnRNP A1 binds and stabil

SUBMITTER: Gupta A 

PROVIDER: S-EPMC12396317 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature