{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T03:22:37Z","timestamp":1783567357738,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1010101","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000}}],"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["ID14974"],"award-info":[{"award-number":["ID14974"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["ID16173"],"award-info":[{"award-number":["ID16173"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Glutamine analogs are potent suppressors of general glutamine metabolism with anti-cancer activity. 6-diazo-5-oxo-L-norleucine (DON) is an orally available glutamine analog which has been recently improved by structural modification for cancer treatment. Here, we explored the chemogenomic landscape of DON sensitivity using budding yeast as model organism. We identify evolutionarily conserved proteins that mediate cell resistance to glutamine analogs, namely Ura8<jats:sup>CTPS1\/2<\/jats:sup>, Hpt1<jats:sup>HPRT1<\/jats:sup>, Mec1<jats:sup>ATR<\/jats:sup>, Rad53<jats:sup>CHK1\/CHK2<\/jats:sup> and Rtg1. We describe a function of Ura8 as inducible CTP synthase responding to inhibition of glutamine metabolism and propose a model for its regulation by CTP levels and Nrd1-dependent transcription termination at a cryptic unstable transcript. Disruption of the inducible CTP synthase under DON exposure hyper-activates the Mec1-Rad53 DNA damage response (DDR) pathway, which prevents chromosome breakage. Simultaneous inhibition of CTP synthase and Mec1 kinase synergistically sensitizes cells to DON, whereas CTP synthase over-expression hampers DDR mutant sensitivity. Using genome-wide suppressor screening, we identify factors promoting DON-induced CTP depletion (TORC1, glutamine transporter) and DNA breakage in DDR mutants. Together, our results identify CTP regulation and the Mec1-Rad53 DDR axis as key glutamine analog response pathways, and provide a rationale for the combined targeting of glutamine and CTP metabolism in DDR-deficient cancers.<\/jats:p>","DOI":"10.1371\/journal.pgen.1010101","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T19:29:26Z","timestamp":1646335766000},"page":"e1010101","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["CTP sensing and Mec1ATR-Rad53CHK1\/CHK2 mediate a two-layered response to inhibition of glutamine metabolism"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8683-0827","authenticated-orcid":true,"given":"Arta","family":"Ajazi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5340-7854","authenticated-orcid":true,"given":"Ramveer","family":"Choudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1217-4046","authenticated-orcid":true,"given":"Laura","family":"Tronci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4842-6556","authenticated-orcid":true,"given":"Angela","family":"Bachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6656-996X","authenticated-orcid":true,"given":"Christopher","family":"Bruhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,3]]},"reference":[{"key":"pgen.1010101.ref001","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nrclinonc.2017.1","article-title":"Cancer metabolism: a therapeutic perspective","volume":"14","author":"UE Martinez-Outschoorn","year":"2017","journal-title":"Nat Rev Clin Oncol"},{"key":"pgen.1010101.ref002","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.4155\/fmc.13.130","article-title":"Therapeutic strategies impacting cancer cell glutamine metabolism","volume":"5","author":"MJ Lukey","year":"2013","journal-title":"Future Med Chem"},{"key":"pgen.1010101.ref003","first-page":"69","article-title":"Glutamine antagonist with diet deficient in glutamine and aspartate reduce tumor growth","volume":"39","author":"K Yoshioka","year":"1992","journal-title":"Tokushima J Exp Med"},{"key":"pgen.1010101.ref004","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1158\/1535-7163.MCT-17-1148","article-title":"We\u2019re Not \"DON\" Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine.","volume":"17","author":"KM Lemberg","year":"2018","journal-title":"Mol Cancer Ther"},{"key":"pgen.1010101.ref005","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1016\/j.tranon.2019.05.013","article-title":"Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma","volume":"12","author":"AR Hanaford","year":"2019","journal-title":"Transl Oncol"},{"key":"pgen.1010101.ref006","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1126\/science.aav2588","article-title":"Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion","volume":"366","author":"RD Leone","year":"2019","journal-title":"Science"},{"key":"pgen.1010101.ref007","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cllc.2013.09.001","article-title":"Altered glutamine metabolism and therapeutic opportunities for lung cancer","volume":"15","author":"A Mohamed","year":"2014","journal-title":"Clin Lung Cancer"},{"key":"pgen.1010101.ref008","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s42003-019-0455-x","article-title":"Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma","volume":"2","author":"P Mukherjee","year":"2019","journal-title":"Commun Biol"},{"key":"pgen.1010101.ref009","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/S0076-6879(77)46049-X","article-title":"Glutamine binding sites","volume":"46","author":"LM Pinkus","year":"1977","journal-title":"Methods Enzymol"},{"key":"pgen.1010101.ref010","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.molcel.2012.05.043","article-title":"Glutaminolysis activates Rag-mTORC1 signaling","volume":"47","author":"RV Duran","year":"2012","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref011","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.celrep.2019.08.076","article-title":"Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer","volume":"29","author":"MJ Lukey","year":"2019","journal-title":"Cell Rep"},{"key":"pgen.1010101.ref012","doi-asserted-by":"crossref","first-page":"9342","DOI":"10.1074\/jbc.RA119.008180","article-title":"Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells","volume":"294","author":"LMD Reis","year":"2019","journal-title":"J Biol Chem"},{"key":"pgen.1010101.ref013","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1186\/s12885-020-06885-3","article-title":"Pyruvate anaplerosis is a mechanism of resistance to pharmacological glutaminase inhibition in triple-receptor negative breast cancer","volume":"20","author":"DC Singleton","year":"2020","journal-title":"BMC Cancer"},{"key":"pgen.1010101.ref014","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.chembiol.2017.08.028","article-title":"Targeting Metabolism for Cancer Therapy","volume":"24","author":"A Luengo","year":"2017","journal-title":"Cell Chem Biol"},{"key":"pgen.1010101.ref015","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.canlet.2019.11.013","article-title":"Dysregulation of de novo nucleotide biosynthetic pathway enzymes in cancer and targeting opportunities","volume":"470","author":"AD Robinson","year":"2020","journal-title":"Cancer Lett"},{"key":"pgen.1010101.ref016","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/35087613","article-title":"The DNA replication checkpoint response stabilizes stalled replication forks","volume":"412","author":"M Lopes","year":"2001","journal-title":"Nature"},{"key":"pgen.1010101.ref017","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1101\/gad.256958.114","article-title":"Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice","volume":"29","author":"AJ Lopez-Contreras","year":"2015","journal-title":"Genes Dev"},{"key":"pgen.1010101.ref018","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1093\/emboj\/20.13.3544","article-title":"The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1\/Rad53 kinase cascade during growth and in response to DNA damage","volume":"20","author":"X Zhao","year":"2001","journal-title":"EMBO J"},{"key":"pgen.1010101.ref019","first-page":"4255","article-title":"ATM and ATR signaling at a glance","volume":"128","author":"P Awasthi","year":"2015","journal-title":"J Cell Sci"},{"key":"pgen.1010101.ref020","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41392-020-0150-x","article-title":"DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer","volume":"5","author":"RX Huang","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"pgen.1010101.ref021","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nrm2852","article-title":"Maintaining genome stability at the replication fork","volume":"11","author":"D Branzei","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pgen.1010101.ref022","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1126\/science.1071398","article-title":"ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones","volume":"297","author":"RS Cha","year":"2002","journal-title":"Science"},{"key":"pgen.1010101.ref023","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0960-9822(00)00447-4","article-title":"Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice","volume":"10","author":"A de Klein","year":"2000","journal-title":"Curr Biol"},{"key":"pgen.1010101.ref024","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1101\/gad.14.12.1448","article-title":"Chk1 is an essential kinase that is regulated by Atr and required for the G(2)\/M DNA damage checkpoint","volume":"14","author":"Q Liu","year":"2000","journal-title":"Genes Dev"},{"key":"pgen.1010101.ref025","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41571-018-0114-z","article-title":"State-of-the-art strategies for targeting the DNA damage response in cancer","volume":"16","author":"PG Pilie","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"pgen.1010101.ref026","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1126\/science.285.5429.901","article-title":"Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis","volume":"285","author":"EA Winzeler","year":"1999","journal-title":"Science"},{"key":"pgen.1010101.ref027","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/BF00281793","article-title":"Use of synthetic lethal mutants to clone and characterize a novel CTP synthetase gene in Saccharomyces cerevisiae","volume":"242","author":"O Ozier-Kalogeropoulos","year":"1994","journal-title":"Mol Gen Genet"},{"key":"pgen.1010101.ref028","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/genetics\/147.2.383","article-title":"The isolation and characterization of Saccharomyces cerevisiae mutants that constitutively express purine biosynthetic genes","volume":"147","author":"ML Guetsova","year":"1997","journal-title":"Genetics"},{"key":"pgen.1010101.ref029","doi-asserted-by":"crossref","first-page":"6784","DOI":"10.1073\/pnas.102687599","article-title":"The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine","volume":"99","author":"JL Crespo","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1010101.ref030","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.molcel.2020.02.021","article-title":"Mec1 Is Activated at the Onset of Normal S Phase by Low-dNTP Pools Impeding DNA Replication","volume":"78","author":"R Forey","year":"2020","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref031","doi-asserted-by":"crossref","first-page":"24982","DOI":"10.1074\/jbc.270.42.24982","article-title":"Differential biochemical regulation of the URA7- and URA8-encoded CTP synthetases from Saccharomyces cerevisiae","volume":"270","author":"AK Nadkarni","year":"1995","journal-title":"J Biol Chem"},{"key":"pgen.1010101.ref032","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/0092-8674(89)90584-9","article-title":"Elevated recombination rates in transcriptionally active DNA","volume":"56","author":"BJ Thomas","year":"1989","journal-title":"Cell"},{"key":"pgen.1010101.ref033","doi-asserted-by":"crossref","first-page":"E4442","DOI":"10.1073\/pnas.1618714114","article-title":"Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis","volume":"114","author":"TT Schmidt","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1010101.ref034","doi-asserted-by":"crossref","first-page":"12171","DOI":"10.1073\/pnas.0403341101","article-title":"Detection of the mycophenolate-inhibited form of IMP dehydrogenase in vivo","volume":"101","author":"CC McPhillips","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1010101.ref035","doi-asserted-by":"crossref","first-page":"14983","DOI":"10.1074\/jbc.270.25.14983","article-title":"Phosphorylation of CTP synthetase from Saccharomyces cerevisiae by protein kinase C","volume":"270","author":"WL Yang","year":"1995","journal-title":"J Biol Chem"},{"key":"pgen.1010101.ref036","doi-asserted-by":"crossref","first-page":"28777","DOI":"10.1074\/jbc.271.46.28777","article-title":"Phosphorylation and regulation of CTP synthetase from Saccharomyces cerevisiae by protein kinase A","volume":"271","author":"WL Yang","year":"1996","journal-title":"J Biol Chem"},{"key":"pgen.1010101.ref037","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S1097-2765(00)80277-4","article-title":"A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools","volume":"2","author":"X Zhao","year":"1998","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref038","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.1038\/s41467-020-17961-4","article-title":"The Rad53(CHK1\/CHK2)-Spt21(NPAT) and Tel1(ATM) axes couple glucose tolerance to histone dosage and subtelomeric silencing","volume":"11","author":"C Bruhn","year":"2020","journal-title":"Nat Commun"},{"key":"pgen.1010101.ref039","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0092-8674(03)00896-1","article-title":"A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae","volume":"115","author":"A Gunjan","year":"2003","journal-title":"Cell"},{"key":"pgen.1010101.ref040","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1128\/MCB.19.1.882","article-title":"Activation of transcription by metabolic intermediates of the pyrimidine biosynthetic pathway","volume":"19","author":"PJ Flynn","year":"1999","journal-title":"Mol Cell Biol"},{"key":"pgen.1010101.ref041","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1038\/emboj.2008.165","article-title":"Mutations of RNA polymerase II activate key genes of the nucleoside triphosphate biosynthetic pathways","volume":"27","author":"M Kwapisz","year":"2008","journal-title":"EMBO J"},{"key":"pgen.1010101.ref042","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1128\/MCB.00380-08","article-title":"Properties of an intergenic terminator and start site switch that regulate IMD2 transcription in yeast","volume":"28","author":"MH Jenks","year":"2008","journal-title":"Mol Cell Biol"},{"key":"pgen.1010101.ref043","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.molcel.2008.05.018","article-title":"Regulation of a eukaryotic gene by GTP-dependent start site selection and transcription attenuation","volume":"31","author":"JN Kuehner","year":"2008","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref044","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.molcel.2008.08.010","article-title":"Futile cycle of transcription initiation and termination modulates the response to nucleotide shortage in S. cerevisiae","volume":"31","author":"M Thiebaut","year":"2008","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref045","doi-asserted-by":"crossref","first-page":"e1006863","DOI":"10.1371\/journal.pgen.1006863","article-title":"Transcriptomes of six mutants in the Sen1 pathway reveal combinatorial control of transcription termination across the Saccharomyces cerevisiae genome","volume":"13","author":"X Chen","year":"2017","journal-title":"PLoS Genet"},{"key":"pgen.1010101.ref046","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-1-61779-129-1_11","article-title":"In vivo site-specific mutagenesis and gene collage using the delitto perfetto system in yeast Saccharomyces cerevisiae","volume":"745","author":"S Stuckey","year":"2011","journal-title":"Methods Mol Biol"},{"key":"pgen.1010101.ref047","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cell.2004.06.013","article-title":"Exploration of essential gene functions via titratable promoter alleles","volume":"118","author":"S Mnaimneh","year":"2004","journal-title":"Cell"},{"key":"pgen.1010101.ref048","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"D Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pgen.1010101.ref049","doi-asserted-by":"crossref","first-page":"e85","DOI":"10.1093\/nar\/gkp1141","article-title":"Quantitation of cellular deoxynucleoside triphosphates","volume":"38","author":"P Ferraro","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"pgen.1010101.ref050","doi-asserted-by":"crossref","first-page":"11113","DOI":"10.1074\/jbc.271.19.11113","article-title":"Regulation of yeast CTP synthetase activity by protein kinase C","volume":"271","author":"WL Yang","year":"1996","journal-title":"J Biol Chem"},{"key":"pgen.1010101.ref051","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/ncb2087","article-title":"The metabolic enzyme CTP synthase forms cytoskeletal filaments","volume":"12","author":"M Ingerson-Mahar","year":"2010","journal-title":"Nat Cell Biol"},{"key":"pgen.1010101.ref052","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S1673-8527(09)60046-1","article-title":"Intracellular compartmentation of CTP synthase in Drosophila","volume":"37","author":"JL Liu","year":"2010","journal-title":"J Genet Genomics"},{"key":"pgen.1010101.ref053","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1083\/jcb.201003001","article-title":"Identification of novel filament-forming proteins in Saccharomyces cerevisiae and Drosophila melanogaster","volume":"190","author":"C Noree","year":"2010","journal-title":"J Cell Biol"},{"key":"pgen.1010101.ref054","doi-asserted-by":"crossref","first-page":"12769","DOI":"10.1093\/nar\/gkab1146","article-title":"Elongating RNA polymerase II and RNA:DNA hybrids hinder fork progression and gene expression at sites of head-on replication-transcription collisions","volume":"49","author":"L Zardoni","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"pgen.1010101.ref055","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.molcel.2012.03.001","article-title":"Preventing replication stress to maintain genome stability: resolving conflicts between replication and transcription","volume":"45","author":"R Bermejo","year":"2012","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref056","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1101\/gad.324517.119","article-title":"Transcription-mediated replication hindrance: a major driver of genome instability","volume":"33","author":"B Gomez-Gonzalez","year":"2019","journal-title":"Genes Dev"},{"key":"pgen.1010101.ref057","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.molcel.2014.10.020","article-title":"Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability","volume":"56","author":"J Sollier","year":"2014","journal-title":"Mol Cell"},{"key":"pgen.1010101.ref058","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/nature13386","article-title":"CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation","volume":"510","author":"E Martin","year":"2014","journal-title":"Nature"},{"key":"pgen.1010101.ref059","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/157489212798358001","article-title":"Expanding targets for a metabolic therapy of cancer","volume":"7","author":"D Covini","year":"2012","journal-title":"L-asparaginase. Recent Pat Anticancer Drug Discov"},{"key":"pgen.1010101.ref060","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1158\/1078-0432.CCR-12-2334","article-title":"SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival","volume":"19","author":"M Hassanein","year":"2013","journal-title":"Clin Cancer Res"},{"key":"pgen.1010101.ref061","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2008.11.044","article-title":"Bidirectional transport of amino acids regulates mTOR and autophagy","volume":"136","author":"P Nicklin","year":"2009","journal-title":"Cell"},{"key":"pgen.1010101.ref062","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.cell.2019.11.031","article-title":"Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery","volume":"181","author":"GM Burslem","year":"2020","journal-title":"Cell"},{"key":"pgen.1010101.ref063","doi-asserted-by":"crossref","DOI":"10.3390\/molecules24061140","article-title":"DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents.","volume":"24","author":"MV Raimondi","year":"2019","journal-title":"Molecules"},{"key":"pgen.1010101.ref064","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1002\/cbic.201600405","article-title":"Exploring the Potent Inhibition of CTP Synthase by Gemcitabine-5\u2019-Triphosphate","volume":"17","author":"GD McCluskey","year":"2016","journal-title":"Chembiochem"},{"key":"pgen.1010101.ref065","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.bbrc.2018.01.107","article-title":"Leflunomide: A promising drug with good antitumor potential","volume":"496","author":"C Zhang","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"pgen.1010101.ref066","doi-asserted-by":"crossref","first-page":"107518","DOI":"10.1016\/j.pharmthera.2020.107518","article-title":"Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy","volume":"210","author":"L Gorecki","year":"2020","journal-title":"Pharmacol Ther"},{"key":"pgen.1010101.ref067","doi-asserted-by":"crossref","first-page":"e2002810","DOI":"10.1371\/journal.pbio.2002810","article-title":"Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes","volume":"15","author":"TQ Tran","year":"2017","journal-title":"PLoS Biol"},{"key":"pgen.1010101.ref068","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13045-019-0754-1","article-title":"Targeting mTOR for cancer therapy","volume":"12","author":"H Hua","year":"2019","journal-title":"J Hematol Oncol"},{"key":"pgen.1010101.ref069","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.18632\/oncotarget.2964","article-title":"Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers","volume":"6","author":"T Bihani","year":"2015","journal-title":"Oncotarget"},{"key":"pgen.1010101.ref070","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1186\/s12885-015-1202-4","article-title":"Control of the MYC-eIF4E axis plus mTOR inhibitor treatment in small cell lung cancer","volume":"15","author":"M Matsumoto","year":"2015","journal-title":"BMC Cancer"},{"key":"pgen.1010101.ref071","article-title":"MYC up-regulation confers resistance to everolimus and establishes vulnerability to cyclin dependent kinase inhibitors in pancreatic neuroendocrine neoplasms cells","author":"F Terracciano","year":"2020","journal-title":"Neuroendocrinology"},{"key":"pgen.1010101.ref072","doi-asserted-by":"crossref","first-page":"13816","DOI":"10.1038\/s41598-017-14124-2","article-title":"FTY720-induced endocytosis of yeast and human amino acid transporters is preceded by reduction of their inherent activity and TORC1 inhibition","volume":"7","author":"C Barthelemy","year":"2017","journal-title":"Sci Rep"},{"key":"pgen.1010101.ref073","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1126\/science.1065810","article-title":"Systematic genetic analysis with ordered arrays of yeast deletion mutants","volume":"294","author":"AH Tong","year":"2001","journal-title":"Science"},{"key":"pgen.1010101.ref074","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1534\/g3.113.009431","article-title":"gitter: a robust and accurate method for quantification of colony sizes from plate images","volume":"4","author":"O Wagih","year":"2014","journal-title":"G3 (Bethesda)"},{"key":"pgen.1010101.ref075","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/nmeth.1534","article-title":"Quantitative analysis of fitness and genetic interactions in yeast on a genome scale","volume":"7","author":"A Baryshnikova","year":"2010","journal-title":"Nat Methods"},{"key":"pgen.1010101.ref076","doi-asserted-by":"crossref","first-page":"493","DOI":"10.4161\/cc.7.4.5323","article-title":"Characterization of the activation domain of the Rad53 checkpoint kinase","volume":"7","author":"S Fiorani","year":"2008","journal-title":"Cell Cycle"},{"key":"pgen.1010101.ref077","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S0076-6879(10)70016-1","article-title":"Mass spectrometry-based metabolomics of yeast","volume":"470","author":"CA Crutchfield","year":"2010","journal-title":"Methods Enzymol"},{"key":"pgen.1010101.ref078","doi-asserted-by":"crossref","first-page":"5810","DOI":"10.1038\/s41598-019-42118-9","article-title":"Evaluation of an untargeted nano-liquid chromatography-mass spectrometry approach to expand coverage of low molecular weight dissolved organic matter in Arctic soil","volume":"9","author":"MP Ladd","year":"2019","journal-title":"Sci Rep"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1010101","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010101","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T17:41:46Z","timestamp":1647366106000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1010101"}},"subtitle":[],"editor":[{"given":"Alan G.","family":"Hinnebusch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,3,3]]},"references-count":78,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1010101","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pgen.1010101","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,3]]}}}