{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTrimethylguanosine synthase 1 (TGS1) belongs to a conserved protein family that features isoforms with an RNA methyltransferase domain; these isoforms are distributed between the nucleus and cytoplasm, reflecting distinct roles in RNA metabolism. TGS1 catalyzes the conversion of the standard 7‐methylguanosine (m⁷G) cap present on spliceosomal small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs) and telomerase RNA into a 2,2,7‐trimethylguanosine (TMG) cap. Structural investigations have revealed that its catalytic domain displays the canonical class I methyltransferase fold augmented by a unique N‑terminal α‑helical segment essential for m⁷G cap recognition and binding, thereby defining the mechanism underlying its methyltransferase activity."}, {"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": "\nGenetic and biochemical analyses in yeast and mammalian systems have further delineated critical aspects of TGS1 function. Mutational studies underscore the requirement for specific amino acid contacts—including a pivotal π‑cation interaction and other key residues engaging the cap triphosphate—to sustain efficient methylation. Moreover, TGS1 self‐association—mediated by its N‑terminal region—emerges as a prerequisite for both optimal enzymatic activity and proper nucleolar localization, fostering accurate processing of sn(o)RNAs when redundant splicing factors are absent."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in snRNP biogenesis, TGS1 influences several broader aspects of RNA metabolism and cellular homeostasis. In telomerase RNA biogenesis, TGS1‐mediated cap hypermethylation limits hTR accumulation, thereby restraining telomerase assembly and telomere elongation. Loss‑of‑function studies in diverse organisms—including Caenorhabditis elegans, Drosophila melanogaster and Danio rerio—demonstrate that impaired TGS1 activity leads to neurological defects reminiscent of SMN deficiency. Furthermore, in adipose tissue, altered TGS1 levels have been linked to changes in adipogenesis and whole‑body energy metabolism, suggesting its potential as a target in obesity‐related metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Izzet Enünlü, Gábor Pápai, Imre Cserpán, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Different isoforms of PRIP-interacting protein with methyltransferase domain/trimethylguanosine synthase localizes to the cytoplasm and nucleus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(03)01514-6"}], "href": "https://doi.org/10.1016/s0006-291x(03"}, {"type": "t", "text": "01514-6) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12943661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12943661"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Cyrille Girard, Céline Verheggen, Henry Neel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of a short isoform of human Tgs1 hypermethylase associating with small nucleolar ribonucleoprotein core proteins and produced by limited proteolytic processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704209200"}], "href": "https://doi.org/10.1074/jbc.M704209200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18039666"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18039666"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Stéphane Hausmann, Sushuang Zheng, Michael Costanzo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic and biochemical analysis of yeast and human cap trimethylguanosine synthase: functional overlap of 2,2,7-trimethylguanosine caps, small nuclear ribonucleoprotein components, pre-mRNA splicing factors, and RNA decay pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M806127200"}], "href": "https://doi.org/10.1074/jbc.M806127200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18775984"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18775984"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Thomas Monecke, Achim Dickmanns, Anja Strasser, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure analysis of the conserved methyltransferase domain of human trimethylguanosine synthase TGS1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Crystallogr D Biol Crystallogr (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1107/S0907444909003102"}], "href": "https://doi.org/10.1107/S0907444909003102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19307714"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19307714"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Thomas Monecke, Achim Dickmanns, Ralf Ficner "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for m7G-cap hypermethylation of small nuclear, small nucleolar and telomerase RNA by the dimethyltransferase TGS1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkp249"}], "href": "https://doi.org/10.1093/nar/gkp249"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19386620"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19386620"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jonathan Chang, Beate Schwer, Stewart Shuman "}, {"type": "b", "children": [{"type": "t", "text": "Mutational analyses of trimethylguanosine synthase (Tgs1) and Mud2: proteins implicated in pre-mRNA splicing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1261/rna.2082610"}], "href": "https://doi.org/10.1261/rna.2082610"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20360394"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20360394"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kum-Loong Boon, Michael David Pearson, Martin Koš "}, {"type": "b", "children": [{"type": "t", "text": "Self-association of Trimethylguanosine Synthase Tgs1 is required for efficient snRNA/snoRNA trimethylation and pre-rRNA processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep11282"}], "href": "https://doi.org/10.1038/srep11282"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26074133"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26074133"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Lu Chen, Caitlin M Roake, Alessandra Galati, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of Human TGS1 Hypermethylase Promotes Increased Telomerase RNA and Telomere Elongation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.01.004"}], "href": "https://doi.org/10.1016/j.celrep.2020.01.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32023455"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32023455"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Lu Chen, Caitlin M Roake, Paolo Maccallini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGS1 impacts snRNA 3'-end processing, ameliorates survival motor neuron-dependent neurological phenotypes in vivo and prevents neurodegeneration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkac659"}], "href": "https://doi.org/10.1093/nar/gkac659"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35947650"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35947650"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Rebecca Kristina Edwin, Lavanya Prakash Acharya, Sujay K Maity, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGS1/PIMT knockdown reduces lipid accumulation in adipocytes, limits body weight gain and promotes insulin sensitivity in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Basis Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2023.166896"}], "href": "https://doi.org/10.1016/j.bbadis.2023.166896"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37751782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37751782"}]}]}]}