{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:10:15Z","timestamp":1783591815462,"version":"3.55.0"},"reference-count":77,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Science","award":["R35-GM128562"],"award-info":[{"award-number":["R35-GM128562"]}]},{"name":"National Institute of General Medical Science","award":["F31-GM146446"],"award-info":[{"award-number":["F31-GM146446"]}]},{"name":"National Institute of General Medical Science","award":["R01-GM105978"],"award-info":[{"award-number":["R01-GM105978"]}]},{"name":"National Institute of General Medical Science","award":["R35-ES030396"],"award-info":[{"award-number":["R35-ES030396"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Telomere biology disorders (TBDs) are a spectrum of diseases that arise from mutations in genes responsible for maintaining telomere integrity. Human telomerase reverse transcriptase (hTERT) adds nucleotides to chromosome ends and is frequently mutated in individuals with TBDs. Previous studies have provided insight into how relative changes in hTERT activity can lead to pathological outcomes. However, the underlying mechanisms describing how disease-associated variants alter the physicochemical steps of nucleotide insertion remain poorly understood. To address this, we applied single-turnover kinetics and computer simulations to the Tribolium castaneum TERT (tcTERT) model system and characterized the nucleotide insertion mechanisms of six disease-associated variants. Each variant had distinct consequences on tcTERT\u2019s nucleotide insertion mechanism, including changes in nucleotide binding affinity, rates of catalysis, or ribonucleotide selectivity. Our computer simulations provide insight into how each variant disrupts active site organization, such as suboptimal positioning of active site residues, destabilization of the DNA 3\u2032 terminus, or changes in nucleotide sugar pucker. Collectively, this work provides a holistic characterization of the nucleotide insertion mechanisms for multiple disease-associated TERT variants and identifies additional functions of key active site residues during nucleotide insertion.<\/jats:p>","DOI":"10.3390\/genes14020281","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T03:21:54Z","timestamp":1674616914000},"page":"281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Altered Nucleotide Insertion Mechanisms of Disease-Associated TERT Variants"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2295-3817","authenticated-orcid":false,"given":"Griffin A.","family":"Welfer","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA"},{"name":"University of Kansas Cancer Center, Kansas City, KS 66103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veniamin A.","family":"Borin","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences and High-Performance Computing Center, Oklahoma State University, Stillwater, OK 74077, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4225-3810","authenticated-orcid":false,"given":"Luis M.","family":"Cortez","sequence":"additional","affiliation":[{"name":"University of Kansas Cancer Center, Kansas City, KS 66103, USA"},{"name":"Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6470-2189","authenticated-orcid":false,"given":"Patricia L.","family":"Opresko","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, and UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratul K.","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences and High-Performance Computing Center, Oklahoma State University, Stillwater, OK 74077, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1449-4710","authenticated-orcid":false,"given":"Bret D.","family":"Freudenthal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA"},{"name":"University of Kansas Cancer Center, Kansas City, KS 66103, USA"},{"name":"Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6622","DOI":"10.1073\/pnas.85.18.6622","article-title":"A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes","volume":"85","author":"Moyzis","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1101\/gad.1346005","article-title":"Shelterin: The protein complex that shapes and safeguards human telomeres","volume":"19","year":"2005","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0022-5193(73)90198-7","article-title":"A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon","volume":"41","author":"Olovnikov","year":"1973","journal-title":"J. Theor. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/0014-4827(65)90211-9","article-title":"The Limited In Vitro Lifetime of Human Diploid Cell Strains","volume":"37","author":"Hayflick","year":"1965","journal-title":"Exp. Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1093\/carcin\/21.3.477","article-title":"The role of senescence and immortalization in carcinogenesis","volume":"21","author":"Reddel","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/0092-8674(85)90170-9","article-title":"Identification of a specific telomere terminal transferase activity in Tetrahymena extracts","volume":"43","author":"Greider","year":"1985","journal-title":"Cell"},{"key":"ref_7","first-page":"414","article-title":"Alternative splicing regulates telomerase repression","volume":"22","author":"Barranco","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1126\/science.7605428","article-title":"Specific association of human telomerase activity with immortal cells and cancer","volume":"266","author":"Kim","year":"1994","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/S0959-8049(97)00062-2","article-title":"A survey of telomerase activity in human cancer","volume":"33","author":"Shay","year":"1997","journal-title":"Eur. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(00)81683-9","article-title":"The hallmarks of cancer","volume":"100","author":"Hanahan","year":"2000","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100064","DOI":"10.1074\/jbc.REV120.014017","article-title":"Molecular mechanisms of telomere biology disorders","volume":"296","author":"Grill","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1097\/GIM.0b013e3181f415b5","article-title":"The genetics and clinical manifestations of telomere biology disorders","volume":"12","author":"Savage","year":"2010","journal-title":"Genet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"15960","DOI":"10.1073\/pnas.0508124102","article-title":"Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita","volume":"102","author":"Armanios","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJMoa066157","article-title":"Telomerase mutations in families with idiopathic pulmonary fibrosis","volume":"356","author":"Armanios","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1080\/15476286.2015.1094596","article-title":"The molecular genetics of the telomere biology disorders","volume":"13","author":"Bertuch","year":"2016","journal-title":"RNA Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41586-018-0062-x","article-title":"Cryo-EM structure of substrate-bound human telomerase holoenzyme","volume":"557","author":"Nguyen","year":"2018","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/s41586-021-03415-4","article-title":"Structure of human telomerase holoenzyme with bound telomeric DNA","volume":"593","author":"Ghanim","year":"2021","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a003558","DOI":"10.1101\/cshperspect.a003558","article-title":"Telomerase: An RNP enzyme synthesizes DNA","volume":"3","author":"Blackburn","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1038\/s41422-021-00586-7","article-title":"Zipper head mechanism of telomere synthesis by human telomerase","volume":"31","author":"Wan","year":"2021","journal-title":"Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1126\/science.1138596","article-title":"Protein composition of catalytically active human telomerase from immortal cells","volume":"315","author":"Cohen","year":"2007","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/0092-8674(87)90576-9","article-title":"The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity","volume":"51","author":"Greider","year":"1987","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e55438","DOI":"10.7554\/eLife.55438","article-title":"Mechanisms of nucleotide selection by telomerase","volume":"9","author":"Schaich","year":"2020","journal-title":"eLife"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1101\/gad.1140303","article-title":"Template boundary definition in mammalian telomerase","volume":"17","author":"Chen","year":"2003","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/nsmb.2174","article-title":"The RNA accordion model for template positioning by telomerase RNA during telomeric DNA synthesis","volume":"18","author":"Berman","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1146\/annurev-biochem-061516-045019","article-title":"Telomerase Mechanism of Telomere Synthesis","volume":"86","author":"Wu","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ymeth.2016.08.002","article-title":"Quantitative assays for measuring human telomerase activity and DNA binding properties","volume":"114","author":"Tomlinson","year":"2017","journal-title":"Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4037","DOI":"10.1021\/bi982249n","article-title":"Regulation of catalytic activity and processivity of human telomerase","volume":"38","author":"Sun","year":"1999","journal-title":"Biochemistry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8969","DOI":"10.1093\/nar\/gkt653","article-title":"Many disease-associated variants of hTERT retain high telomerase enzymatic activity","volume":"41","author":"Zaug","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bagshaw, C.R., Hentschel, J., and Stone, M.D. (2021). The Processivity of Telomerase: Insights from Kinetic Simulations and Analyses. Molecules, 26.","DOI":"10.3390\/molecules26247532"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1261\/rna.077255.120","article-title":"Folding heterogeneity in the essential human telomerase RNA three-way junction","volume":"26","author":"Palka","year":"2020","journal-title":"RNA"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hentschel, J. (2021). Multiplexed single-molecule analysis of human telomerase synthesizing DNA. bioRxiv.","DOI":"10.1101\/2021.06.25.449954"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/bs.mie.2017.04.002","article-title":"Analyzing the Catalytic Activities and Interactions of Eukaryotic Translesion Synthesis Polymerases","volume":"592","author":"Powers","year":"2017","journal-title":"Methods Enzymol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature07283","article-title":"Structure of the Tribolium castaneum telomerase catalytic subunit TERT","volume":"455","author":"Gillis","year":"2008","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.cell.2018.04.038","article-title":"Structure of Telomerase with Telomeric DNA","volume":"173","author":"Jiang","year":"2018","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1093\/nar\/gkx1275","article-title":"Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase","volume":"46","author":"Petrova","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e2116159118","DOI":"10.1073\/pnas.2116159118","article-title":"Flexibility of telomerase in binding the RNA template and DNA telomeric repeat","volume":"119","author":"Choi","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41586-021-03529-9","article-title":"Structures of telomerase at several steps of telomere repeat synthesis","volume":"593","author":"He","year":"2021","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"31078","DOI":"10.1073\/pnas.2011684117","article-title":"A structurally conserved human and Tetrahymena telomerase catalytic core","volume":"117","author":"Wang","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41586-022-04582-8","article-title":"Structure of active human telomerase with telomere shelterin protein TPP1","volume":"604","author":"Liu","year":"2022","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1126\/science.abn6840","article-title":"Structural basis of human telomerase recruitment by TPP1-POT1","volume":"375","author":"Sekne","year":"2022","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1002\/cpnc.98","article-title":"Full Pre-Steady-State Kinetic Analysis of Single Nucleotide Incorporation by DNA Polymerases","volume":"78","author":"Renders","year":"2019","journal-title":"Curr. Protoc. Nucleic Acid Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7.23.1","DOI":"10.1002\/cpnc.2","article-title":"Pre-Steady-State Kinetic Analysis of Single-Nucleotide Incorporation by DNA Polymerases","volume":"65","author":"Su","year":"2016","journal-title":"Curr. Protoc. Nucleic Acid Chem."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"de Leon, A.D., Cronkhite, J.T., Katzenstein, A.L., Godwin, J.D., Raghu, G., Glazer, C.S., Rosenblatt, R.L., Girod, C.E., Garrity, E.R., and Xing, C. (2010). Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010680"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/s41431-018-0112-8","article-title":"Novel variants in Nordic patients referred for genetic testing of telomere-related disorders","volume":"26","author":"Norberg","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1182\/blood-2008-07-166421","article-title":"TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements","volume":"113","author":"Du","year":"2009","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Vulliamy, T.J., Kirwan, M.J., Beswick, R., Hossain, U., Baqai, C., Ratcliffe, A., Marsh, J., Walne, A., and Dokal, I. (2011). Differences in disease severity but similar telomere lengths in genetic subgroups of patients with telomerase and shelterin mutations. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024383"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/nature11282","article-title":"Recurrent R-spondin fusions in colon cancer","volume":"488","author":"Seshagiri","year":"2012","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1126\/science.1208130","article-title":"The mutational landscape of head and neck squamous cell carcinoma","volume":"333","author":"Stransky","year":"2011","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7552","DOI":"10.1073\/pnas.0701009104","article-title":"Adult-onset pulmonary fibrosis caused by mutations in telomerase","volume":"104","author":"Tsakiri","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31411","DOI":"10.1074\/jbc.M114.607432","article-title":"Substrate-induced DNA polymerase \u03b2 activation","volume":"289","author":"Beard","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"25494","DOI":"10.1073\/pnas.2010484117","article-title":"Visualizing Rev1 catalyze protein-template DNA synthesis","volume":"117","author":"Weaver","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","unstructured":"Case, D.A., Berryman, J.T., Betz, R.M., Cerutti, D.S., Cheatham, T.E., Darden, T.A., Duke, R.E., Giese, T.J., Gohlke, H., and G\u00f6tz, A.W. (2015). AMBER 15, University of California."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the accuracy of protein side chain and backbone parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1002\/prot.24135","article-title":"Event detection and sub-state discovery from biomolecular simulations using higher-order statistics: Application to enzyme adenylate kinase","volume":"80","author":"Ramanathan","year":"2012","journal-title":"Proteins"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4184","DOI":"10.1021\/acs.biochem.6b00130","article-title":"Ligand Binding Enhances Millisecond Conformational Exchange in Xylanase B2 from Streptomyces lividans","volume":"55","author":"Gagne","year":"2016","journal-title":"Biochemistry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3293","DOI":"10.1016\/j.csbj.2021.05.035","article-title":"Altered APE1 activity on abasic ribonucleotides is mediated by changes in the nucleoside sugar pucker","volume":"19","author":"Hoitsma","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_57","first-page":"7345","article-title":"AP-endonuclease 1 sculpts DNA through an anchoring tyrosine residue on the DNA intercalating loop","volume":"48","author":"Hoitsma","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Ramanathan, A., and Agarwal, P.K. (2011). Evolutionarily Conserved Linkage between Enzyme Fold, Flexibility, and Catalysis. PLoS Biol., 9.","DOI":"10.1371\/journal.pbio.1001193"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4263","DOI":"10.1021\/acs.biochem.8b00424","article-title":"Modulating enzyme activity by altering protein dynamics with solvent","volume":"57","author":"Duff","year":"2018","journal-title":"Biochemistry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ymeth.2004.03.008","article-title":"Methods for molecular dynamics simulations of protein folding\/unfolding in solution","volume":"34","author":"Beck","year":"2004","journal-title":"Methods"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5864","DOI":"10.1021\/acs.biochem.8b00783","article-title":"Differential substrate recognition by maltose binding proteins influenced by structure and dynamics","volume":"57","author":"Shukla","year":"2018","journal-title":"Biochemistry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/nature11181","article-title":"Watching DNA polymerase eta make a phosphodiester bond","volume":"487","author":"Nakamura","year":"2012","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.cell.2013.05.048","article-title":"Observing a DNA polymerase choose right from wrong","volume":"154","author":"Freudenthal","year":"2013","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"509","DOI":"10.2741\/3941","article-title":"DNA polymerases: Mechanistic insight from biochemical and biophysical studies","volume":"17","author":"Delagoutte","year":"2012","journal-title":"Front. Biosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4267","DOI":"10.1073\/pnas.0608952104","article-title":"Two proton transfers in the transition state for nucleotidyl transfer catalyzed by RNA- and DNA-dependent RNA and DNA polymerases","volume":"104","author":"Castro","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nsmb.1540","article-title":"Nucleic acid polymerases use a general acid for nucleotidyl transfer","volume":"16","author":"Castro","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1183\/13993003.00308-2016","article-title":"Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive","volume":"48","author":"Newton","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2003198","DOI":"10.1183\/13993003.03198-2020","article-title":"Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation","volume":"57","author":"Justet","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1021\/ja00788a038","article-title":"Conformational analysis of the sugar ring in nucleosides and nucleotides. Improved method for the interpretation of proton magnetic resonance coupling constants","volume":"95","author":"Altona","year":"1973","journal-title":"J. Am. Chem. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8205","DOI":"10.1021\/ja00778a043","article-title":"Conformational analysis of the sugar ring in nucleosides and nucleotides. A new description using the concept of pseudorotation","volume":"94","author":"Altona","year":"1972","journal-title":"J. Am. Chem. Soc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"11994","DOI":"10.1021\/bi9014133","article-title":"Impact of sugar pucker on base pair and mispair stability","volume":"48","author":"Williams","year":"2009","journal-title":"Biochemistry"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"24457","DOI":"10.1074\/jbc.M110.132407","article-title":"DNA polymerase \u03b2 ribonucleotide discrimination: Insertion, misinsertion, extension, and coding","volume":"285","author":"Cavanaugh","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5422","DOI":"10.1002\/j.1460-2075.1995.tb00226.x","article-title":"Utilization of ribonucleotides and RNA primers by Tetrahymena telomerase","volume":"14","author":"Collins","year":"1995","journal-title":"EMBO J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1021\/bi101915z","article-title":"Unlocking the sugar \u201csteric gate\u201d of DNA polymerases","volume":"50","author":"Brown","year":"2011","journal-title":"Biochemistry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1093\/nar\/gkw128","article-title":"Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-eta","volume":"44","author":"Genna","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1093\/nar\/gkm002","article-title":"The active site residue Valine 867 in human telomerase reverse transcriptase influences nucleotide incorporation and fidelity","volume":"35","author":"Drosopoulos","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"10693","DOI":"10.1093\/nar\/gkz792","article-title":"A polar filter in DNA polymerases prevents ribonucleotide incorporation","volume":"47","author":"Johnson","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/281\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:12:45Z","timestamp":1760119965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/2\/281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,21]]},"references-count":77,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["genes14020281"],"URL":"https:\/\/doi.org\/10.3390\/genes14020281","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,21]]}}}