{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCytosolic seryl‐tRNA synthetase (SARS1) is best known for its canonical role in translation, where it catalyzes the ligation of serine to its cognate tRNA(Ser)—a critical step for protein biosynthesis. Structural studies of human SARS1 have revealed unique features, including higher eukaryote–specific insertions and extended domains that not only optimize enzymatic activity but also determine substrate recognition (e.g., distinguishing between tRNA(Ser) and the selenocysteine‐accepting tRNA). Moreover, SARS1 shares mechanistic parallels with its mitochondrial counterpart (SARS2), whose impairment causes distinct multisystem mitochondrial disorders; however, SARS1 primarily sustains cytoplasmic protein synthesis (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its primary enzymatic function, SARS1 has emerged as a key noncanonical regulator of gene expression. An appended domain present in vertebrate SARS1 facilitates its translocation to the nucleus where it engages in regulatory complexes—for example, by partnering with transcription factors such as YY1 to negatively control vascular endothelial growth factor A (VEGFA) transcription. This activity, which is further modulated by small molecules and post‐translational modifications that affect nuclear localization (and hence angiogenesis and lipid biosynthesis), has been implicated in vascular development as well as in the anti‐angiogenic response required to constrain tumor growth (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIntriguingly, perturbation of SARS1 function is now linked to human disease. Missense and other pathogenic variants in SARS1 have been associated with intellectual disability, microcephaly, and developmental delay, underscoring its vital role in neurodevelopment. In addition, SARS1 participates in noncanonical translational readthrough events, contributing to the synthesis of C-terminally extended protein isoforms (including those incorporating selenocysteine) and thereby expanding the functional proteome. This emerging facet of SARS1 biology opens potential avenues for therapeutic intervention against genetic disorders caused by premature stop codons (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wiebke Herzog, Katja Müller, Jan Huisken, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SerRS-tRNASec complex structures reveal mechanism of the first step in selenocysteine biosynthesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkv996"}], "href": "https://doi.org/10.1093/nar/gkv996"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26433229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26433229"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiaoling Xu, Yi Shi, Hui-Min Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Unique domain appended to vertebrate tRNA synthetase is essential for vascular development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms1686"}], "href": "https://doi.org/10.1038/ncomms1686"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22353712"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22353712"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Henry Rivera, Elena Martín-Hernández, Aitor Delmiro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Nephrol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2369-14-195"}], "href": "https://doi.org/10.1186/1471-2369-14-195"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24034276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24034276"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Chuan-Yang Fu, Po-Chun Wang, Huai-Jen Tsai "}, {"type": "b", "children": [{"type": "t", "text": "Competitive binding between Seryl-tRNA synthetase/YY1 complex and NFKB1 at the distal segment results in differential regulation of human vegfa promoter activity during angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkw1187"}], "href": "https://doi.org/10.1093/nar/gkw1187"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27913726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27913726"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Gengyi Zou, Xiaotong Zhang, Lun Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Herb-sourced emodin inhibits angiogenesis of breast cancer by targeting VEGFA transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Theranostics (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/thno.43622"}], "href": "https://doi.org/10.7150/thno.43622"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32550907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32550907"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jin Zhao, Hangming Bai, Xiaoyu Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Glucose-sensitive acetylation of Seryl tRNA synthetase regulates lipid synthesis in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Signal Transduct Target Ther (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41392-021-00714-0"}], "href": "https://doi.org/10.1038/s41392-021-00714-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34400610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34400610"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Luciana Musante, Lucia Püttmann, Kimia Kahrizi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.23205"}], "href": "https://doi.org/10.1002/humu.23205"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28236339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28236339"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Kaitlyn M Holman, Anupama K Puppala, Jonathan W Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insights into substrate promiscuity of human seryl-tRNA synthetase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1261/rna.061069.117"}], "href": "https://doi.org/10.1261/rna.061069.117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28808125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28808125"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Nina Bögershausen, Hannah E Krawczyk, Rami A Jamra, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Seryl-tRNA synthetase promotes translational readthrough by mRNA binding and involvement of the selenocysteine incorporation machinery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkad773"}], "href": "https://doi.org/10.1093/nar/gkad773"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37739431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37739431"}]}]}]}