{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPUS1 encodes pseudouridine synthase 1 (Pus1p), an enzyme that catalyzes the isomerization of uridine to pseudouridine in various RNAs. Early studies linked missense mutations in PUS1 to mitochondrial myopathy and sideroblastic anemia (MLASA), where deficient pseudouridylation of mitochondrial (and cytoplasmic) tRNAs impairs oxidative phosphorylation—a defect most notable in skeletal muscle and bone marrow. These findings highlighted the critical role of Pus1p in ensuring proper tRNA modification to support efficient mitochondrial translation and energy production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in tRNA modification, Pus1p has been shown to target mRNAs, mediating pseudouridylation in a structure‐dependent manner. Recent high‐throughput kinetic analyses and in vivo studies have revealed that a specific RNA structural motif directs Pus1p to modify numerous mRNA targets. This modification influences alternative splicing and 3′ end processing, thereby suggesting that Pus1p plays a broader regulatory role in gene expression than initially appreciated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther insights into the enzymology of Pus1p indicate that its active site—composed of highly conserved residues—can tolerate some amino acid substitutions while still retaining significant activity. Detailed mutagenesis studies have demonstrated that proper substrate recognition, particularly through the maintenance of RNA secondary structures such as the anticodon stem-loop and TΨC arm in tRNAs, is essential for pseudouridylation. These findings underscore how both the intrinsic properties of Pus1p and the conformational features of its RNA substrates govern its modification efficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging research now also implicates Pus1p in oncogenesis. Altered levels of pseudouridine in patient serum and urine, as observed in hepatocellular carcinoma (HCC), point to a potential role for PUS1 in cancer pathogenesis, opening new avenues for the exploration of RNA modification pathways as therapeutic targets."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yelena Bykhovskaya, Kari Casas, Emebet Mengesha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/421530"}], "href": "https://doi.org/10.1086/421530"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15108122"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15108122"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jeffrey R Patton, Yelena Bykhovskaya, Emebet Mengesha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M500216200"}], "href": "https://doi.org/10.1074/jbc.M500216200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15772074"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15772074"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Erika Fernandez-Vizarra, Angela Berardinelli, Lucia Valente, et al. 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