| Pseudouridine synthase 7 (PUS7) is a conserved RNA-modifying enzyme of the pseudouridine synthase family that deposits pseudouridine on diverse RNA substrates and functions as an epitranscriptomic regulator of translation and signaling. The protein contains the characteristic catalytic core of pseudouridine synthases and localizes predominantly to the nucleus but can also act on cytoplasmic RNAs, introducing site-specific pseudouridylation on tRNAs, mRNAs and small RNAs with defined sequence and structural contexts. PUS7-dependent pseudouridylation of a subset of tRNAs shapes codon-specific translation by modulating tRNA decoding properties; loss of PUS7 activity reduces pseudouridine levels at defined positions in small RNAs and alters translation of proteins whose codon usage depends on these modified tRNAs, without causing a global shutdown of protein synthesis. In glioblastoma stem cells, PUS7 expression is higher than in normal brain tissue and neural stem cells, and PUS7 regulates translation of TYK2 via pseudouridylated tRNAs, leading to changes in interferon pathway components and STAT1 signaling that affect growth and self-renewal of these cells. Catalytic inactivation or knockdown of PUS7 reduces glioblastoma stem cell proliferation and tumorigenesis, and small-molecule inhibitors that suppress PUS7 enzymatic activity decrease pseudouridine modification in target RNAs and restrain glioblastoma growth in preclinical models, indicating that the catalytic pseudouridylation function is directly linked to tumor-supportive translation programs. Across cancer contexts, PUS7 has been identified as an RNA modification gene with diagnostic and prognostic relevance, where altered expression associates with tumor progression and patient outcome, and transcriptome-wide analyses reveal PUS7-dependent pseudouridine sites in mRNAs that encode regulators of signaling pathways beyond interferon, extending its influence from tRNA-mediated codon bias to direct mRNA structural and stability effects. Structural and functional studies in yeast show that PUS7 catalyzes pseudouridylation at defined positions in snRNA, rRNA and pre-tRNA species and relocates between nucleus and cytoplasm under heat shock, supporting a conserved stress-responsive role in adjusting RNA modification patterns and translation across species. Together, these findings define PUS7 as a nuclear–cytoplasmic pseudouridine synthase with a characteristic catalytic domain architecture that modifies tRNAs and other RNAs to tune codon-specific translation, interferon–STAT1 signaling and stress-responsive RNA metabolism, and its dysregulated activity in glioblastoma and other tumors places it among epitranscriptomic enzymes of interest for mechanistic study and targeted inhibition in cancer biology. |
