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The tRNA Gm18 methyltransferase TARBP1 promotes hepatocellular carcinoma progression via metabolic reprogramming of glutamine

Cell Death & Differentiation volume 31, pages 1219–1234 (2024)Cite this article

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Abstract

Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. Using CRISPR/Cas9 interference (CRISPRi) screening, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a critical regulator involved in glutamine reliance of cancer cell. Consistent with this discovery, TARBP1 amplification and overexpression are frequently observed in various cancers. Knockout of TARBP1 significantly suppresses cell proliferation, colony formation and xenograft tumor growth. Mechanistically, TARBP1 selectively methylates and stabilizes a small subset of tRNAs, which promotes efficient protein synthesis of glutamine transporter-ASCT2 (also known as SLC1A5) and glutamine import to fuel the growth of cancer cell. Moreover, we found that the gene expression of TARBP1 and ASCT2 are upregulated in combination in clinical cohorts and their upregulation is associated with unfavorable prognosis of HCC (hepatocellular carcinoma). Taken together, this study reveals the unexpected role of TARBP1 in coordinating the tRNA availability and glutamine uptake during HCC progression and provides a potential target for tumor therapy.

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Fig. 1: CRISPRi/Cas9 library screening identified TARBP1 as a novel regulator of cancer glutamine metabolism.
Fig. 2: TARBP1 is necessary for tumor growth.
Fig. 3: TARBP1 is the Gm18 methyltransferase targeting tRNAGln-TTG/CTG and tRNASer-TGA/GCT.
Fig. 4: TARBP1 affects mRNA translation possibly by regulating the stability of Gm18-modified tRNAs.
Fig. 5: TARBP1 enhances glutamine metabolism via translation regulation of ASCT2.
Fig. 6: The expression of TARBP1 and ASCT2 is correlated and associated with HCC patient prognosis.

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Data availability

The raw data of this study is available in the GEO database under the accession number: GSE236369.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301–14.

    Article  PubMed  Google Scholar 

  3. Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20:203–22.

    Article  PubMed  Google Scholar 

  4. Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016;23:27–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16:619–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang L, Venneti S, Nagrath D. Glutaminolysis: A Hallmark of Cancer Metabolism. Annu Rev Biomed Eng. 2017;19:163–94.

    Article  CAS  PubMed  Google Scholar 

  7. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10:671–84.

    Article  Google Scholar 

  8. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017;14:11–31.

    Article  CAS  PubMed  Google Scholar 

  9. Yang WH, Qiu Y, Stamatatos O, Janowitz T, Lukey MJ. Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy. Trends Cancer. 2021;7:790–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008;105:18782–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA. The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat Commun. 2016;7:11321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weng H, Huang F, Yu Z, Chen Z, Prince E, Kang Y, et al. The m(6)A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia. Cancer Cell. 2022;40:1566–82.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rich A, RajBhandary UL. Transfer RNA: molecular structure, sequence, and properties. Annu Rev Biochem. 1976;45:805–60.

    Article  CAS  PubMed  Google Scholar 

  15. Giegé R. Toward a more complete view of tRNA biology. Nat Struct Mol Biol. 2008;15:1007–14.

    Article  PubMed  Google Scholar 

  16. Pavon-Eternod M, Gomes S, Geslain R, Dai Q, Rosner MR, Pan T. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 2009;37:7268–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Santos M, Fidalgo A, Varanda AS, Oliveira C, Santos MAS. tRNA Deregulation and Its Consequences in Cancer. Trends Mol Med. 2019;25:853–65.

    Article  CAS  PubMed  Google Scholar 

  18. Orellana EA, Liu Q, Yankova E, Pirouz M, De Braekeleer E, Zhang W, et al. METTL1-mediated m(7)G modification of Arg-TCT tRNA drives oncogenic transformation. Mol Cell. 2021;81:3323–38.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Dai Z, Liu H, Liao J, Huang C, Ren X, Zhu W, et al. N(7)-Methylguanosine tRNA modification enhances oncogenic mRNA translation and promotes intrahepatic cholangiocarcinoma progression. Mol Cell. 2021;81:3339–55.e8.

    Article  CAS  PubMed  Google Scholar 

  20. Thandapani P, Kloetgen A, Witkowski MT, Glytsou C, Lee AK, Wang E, et al. Valine tRNA levels and availability regulate complex I assembly in leukaemia. Nature. 2022;601:428–33.

    Article  CAS  PubMed  Google Scholar 

  21. Earnest-Noble LB, Hsu D, Chen S, Asgharian H, Nandan M, Passarelli MC, et al. Two isoleucyl tRNAs that decode synonymous codons divergently regulate breast cancer metastatic growth by controlling translation of proliferation-regulating genes. Nat Cancer. 2022;3:1484–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Passarelli MC, Pinzaru AM, Asgharian H, Liberti MV, Heissel S, Molina H, et al. Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics. Nat Cell Biol. 2022;24:307–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Koonin EV, Rudd KE. SpoU protein of Escherichia coli belongs to a new family of putative rRNA methylases. Nucleic Acids Res. 1993;21:5519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wu H, Min J, Zeng H, Plotnikov AN. Crystal structure of the methyltransferase ___domain of human TARBP1. Proteins. 2008;72:519–25.

    Article  CAS  PubMed  Google Scholar 

  25. Mistry J, Chuguransky S, Williams L, Qureshi M, Salazar GA, Sonnhammer ELL, et al. Pfam: The protein families database in 2021. Nucleic Acids Res. 2021;49:D412–d19.

    Article  CAS  PubMed  Google Scholar 

  26. Freund I, Buhl DK, Boutin S, Kotter A, Pichot F, Marchand V, et al. 2’-O-methylation within prokaryotic and eukaryotic tRNA inhibits innate immune activation by endosomal Toll-like receptors but does not affect recognition of whole organisms. RNA. 2019;25:869–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sprinzl M, Steegborn C, Hübel F, Steinberg S. Compilation of tRNA sequences and sequences of tRNA genes. Nucleic Acids Res. 1996;24:68–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Persson BC, Jäger G, Gustafsson C. The spoU gene of Escherichia coli, the fourth gene of the spoT operon, is essential for tRNA (Gm18) 2’-O-methyltransferase activity. Nucleic Acids Res. 1997;25:4093–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cavaillé J, Chetouani F, Bachellerie JP. The yeast Saccharomyces cerevisiae YDL112w ORF encodes the putative 2’-O-ribose methyltransferase catalyzing the formation of Gm18 in tRNAs. RNA. 1999;5:66–81.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, et al. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol. 2014;15:554.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol. 2016;18:886–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang Y, Wan X, Hao Y, Zhao Y, Du L, Huang Y, et al. NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells. Cell Commun Signal. 2019;17:77.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lomberk G, Grzenda A, Mathison A, Escande C, Zhang JS, Calvo E, et al. Krüppel-like factor 11 regulates the expression of metabolic genes via an evolutionarily conserved protein interaction ___domain functionally disrupted in maturity onset diabetes of the young. J Biol Chem. 2013;288:17745–58.

    Article  CAS  PubMed  Google Scholar 

  34. Sun N, Shen C, Zhang L, Wu X, Yu Y, Yang X, et al. Hepatic Krüppel-like factor 16 (KLF16) targets PPARα to improve steatohepatitis and insulin resistance. Gut. 2021;70:2183–95.

    Article  CAS  PubMed  Google Scholar 

  35. Ye J, Wang J, Zhang N, Liu Y, Tan L, Xu L. Expression of TARBP1 protein in human non-small-cell lung cancer and its prognostic significance. Oncol Lett. 2018;15:7182–90.

    PubMed  PubMed Central  Google Scholar 

  36. Martínez-Jiménez F, Muiños F, Sentís I, Deu-Pons J, Reyes-Salazar I, Arnedo-Pac C, et al. A compendium of mutational cancer driver genes. Nat Rev Cancer. 2020;20:555–72.

    Article  PubMed  Google Scholar 

  37. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  PubMed  Google Scholar 

  38. de Bruijn I, Kundra R, Mastrogiacomo B, Tran TN, Sikina L, Mazor T, et al. Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal. Cancer Res. 2023;83:3861–67.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, et al. OncoKB: A Precision Oncology Knowledge Base. JCO Precis Oncol. 2017;2017:PO.17.00011.

    PubMed  Google Scholar 

  40. Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, et al. Accelerating Discovery of Functional Mutant Alleles in Cancer. Cancer Discov. 2018;8:174–83.

    Article  CAS  PubMed  Google Scholar 

  41. Delaunay S, Frye M. RNA modifications regulating cell fate in cancer. Nat Cell Biol. 2019;21:552–59.

    Article  CAS  PubMed  Google Scholar 

  42. Gauss DH, Grüter F, Sprinzl M. Compilation of tRNA sequences. Nucleic Acids Res. 1979;6:r1–r19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Loher P, Telonis AG, Rigoutsos I. MINTmap: fast and exhaustive profiling of nuclear and mitochondrial tRNA fragments from short RNA-seq data. Sci Rep. 2017;7:41184.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Suzuki T. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol. 2021;22:375–92.

    Article  CAS  PubMed  Google Scholar 

  45. Pan T. Modifications and functional genomics of human transfer RNA. Cell Res. 2018;28:395–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rezgui VA, Tyagi K, Ranjan N, Konevega AL, Mittelstaet J, Rodnina MV, et al. tRNA tKUUU, tQUUG, and tEUUC wobble position modifications fine-tune protein translation by promoting ribosome A-site binding. Proc Natl Acad Sci USA. 2013;110:12289–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Guzzi N, Cieśla M, Ngoc PCT, Lang S, Arora S, Dimitriou M, et al. Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells. Cell. 2018;173:1204–16.e26.

    Article  CAS  PubMed  Google Scholar 

  48. Ohira T, Minowa K, Sugiyama K, Yamashita S, Sakaguchi Y, Miyauchi K, et al. Reversible RNA phosphorylation stabilizes tRNA for cellular thermotolerance. Nature. 2022;605:372–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nedialkova DD, Leidel SA. Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity. Cell. 2015;161:1606–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Choi J, Grosely R, Prabhakar A, Lapointe CP, Wang J, Puglisi JD. How Messenger RNA and Nascent Chain Sequences Regulate Translation Elongation. Annu Rev Biochem. 2018;87:421–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tenson T, Ehrenberg M. Regulatory nascent peptides in the ribosomal tunnel. Cell. 2002;108:591–4.

    Article  CAS  PubMed  Google Scholar 

  52. Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST, et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018;24:194–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, et al. A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. Cell Metab. 2020;31:267–83.e12.

    Article  CAS  PubMed  Google Scholar 

  54. Liu Y, Zhao T, Li Z, Wang L, Yuan S, Sun L. The role of ASCT2 in cancer: A review. Eur J Pharm. 2018;837:81–87.

    Article  CAS  Google Scholar 

  55. Wu F, Garcia J, Sigman D, Gaynor R. tat regulates binding of the human immunodeficiency virus trans-activating region RNA loop-binding protein TRP-185. Genes Dev. 1991;5:2128–40.

    Article  CAS  PubMed  Google Scholar 

  56. García-Martínez LF, Mavankal G, Peters P, Wu-Baer F, Gaynor RB. Tat functions to stimulate the elongation properties of transcription complexes paused by the duplicated TAR RNA element of human immunodeficiency virus 2. J Mol Biol. 1995;254:350–63.

    Article  PubMed  Google Scholar 

  57. Wu-Baer F, Lane WS, Gaynor RB. The cellular factor TRP-185 regulates RNA polymerase II binding to HIV-1 TAR RNA. EMBO J. 1995;14:5995–6009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wu-Baer F, Lane WS, Gaynor RB. Identification of a group of cellular cofactors that stimulate the binding of RNA polymerase II and TRP-185 to human immunodeficiency virus 1 TAR RNA. J Biol Chem. 1996;271:4201–8.

    Article  CAS  PubMed  Google Scholar 

  59. Feng S, Holland EC. HIV-1 tat trans-activation requires the loop sequence within tar. Nature. 1988;334:165–7.

    Article  CAS  PubMed  Google Scholar 

  60. Ringeard M, Marchand V, Decroly E, Motorin Y, Bennasser Y. FTSJ3 is an RNA 2’-O-methyltransferase recruited by HIV to avoid innate immune sensing. Nature. 2019;565:500–04.

    Article  CAS  PubMed  Google Scholar 

  61. Ayadi L, Galvanin A, Pichot F, Marchand V, Motorin Y. RNA ribose methylation (2’-O-methylation): Occurrence, biosynthesis and biological functions. Biochim Biophys Acta Gene Regul Mech. 2019;1862:253–69.

    Article  CAS  PubMed  Google Scholar 

  62. Jöckel S, Nees G, Sommer R, Zhao Y, Cherkasov D, Hori H, et al. The 2’-O-methylation status of a single guanosine controls transfer RNA-mediated Toll-like receptor 7 activation or inhibition. J Exp Med. 2012;209:235–41.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gehrig S, Eberle ME, Botschen F, Rimbach K, Eberle F, Eigenbrod T, et al. Identification of modifications in microbial, native tRNA that suppress immunostimulatory activity. J Exp Med. 2012;209:225–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rimbach K, Kaiser S, Helm M, Dalpke AH, Eigenbrod T. 2’-O-Methylation within Bacterial RNA Acts as Suppressor of TLR7/TLR8 Activation in Human Innate Immune Cells. J Innate Immun. 2015;7:482–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Berg MD, Brandl CJ. Transfer RNAs: diversity in form and function. RNA Biol. 2021;18:316–39.

    Article  CAS  PubMed  Google Scholar 

  66. Randerath E, Gopalakrishnan AS, Gupta RC, Agrawal HP, Randerath K. Lack of a specific ribose methylation at guanosine 17 in Morris hepatoma 5123D tRNASer1IGA. Cancer Res. 1981;41:2863–7.

    CAS  PubMed  Google Scholar 

  67. Züst R, Cervantes-Barragan L, Habjan M, Maier R, Neuman BW, Ziebuhr J, et al. Ribose 2’-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat Immunol. 2011;12:137–43.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Daffis S, Szretter KJ, Schriewer J, Li J, Youn S, Errett J, et al. 2’-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature. 2010;468:452–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14:500–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Best SA, Gubser PM, Sethumadhavan S, Kersbergen A, Negrón Abril YL, Goldford J, et al. Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer. Cell Metab. 2022;34:874–87.e6.

    Article  CAS  PubMed  Google Scholar 

  71. Terunuma A, Putluri N, Mishra P, Mathé EA, Dorsey TH, Yi M, et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014;124:398–412.

    Article  CAS  PubMed  Google Scholar 

  72. Coloff JL, Murphy JP, Braun CR, Harris IS, Shelton LM, Kami K, et al. Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells. Cell Metab. 2016;23:867–80.

    Article  CAS  PubMed  Google Scholar 

  73. Chen Z, Wang Y, Warden C, Chen S. Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol. 2015;149:118–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu T, Han C, Fang P, Ma Z, Wang X, Chen H, et al. Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma. J Hematol Oncol. 2022;15:141.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Bi J, Chowdhry S, Wu S, Zhang W, Masui K, Mischel PS. Altered cellular metabolism in gliomas - an emerging landscape of actionable co-dependency targets. Nat Rev Cancer. 2020;20:57–70.

    Article  CAS  PubMed  Google Scholar 

  76. Tardito S, Oudin A, Ahmed SU, Fack F, Keunen O, Zheng L, et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Cell Biol. 2015;17:1556–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chothani SP, Adami E, Widjaja AA, Langley SR, Viswanathan S, Pua CJ, et al. A high-resolution map of human RNA translation. Mol Cell. 2022;82:2885–99 e8.

    Article  CAS  PubMed  Google Scholar 

  78. Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2012;41:D590–D96.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Bao W, Kojima KK, Kohany O. Repbase Update, a database of repetitive elements in eukaryotic genomes. Mob DNA. 2015;6:11.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10:R25.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2012;29:15–21.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Pertea M, Pertea GM, Antonescu CM, Chang T-C, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015;33:290–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Liu Q, Shvarts T, Sliz P, Gregory RI. RiboToolkit: an integrated platform for analysis and annotation of ribosome profiling data to decode mRNA translation at codon resolution. Nucleic Acids Res. 2020;48:W218–W29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhong Y, Karaletsos T, Drewe P, Sreedharan VT, Kuo D, Singh K, et al. RiboDiff: detecting changes of mRNA translation efficiency from ribosome footprints. Bioinformatics. 2016;33:139–41.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Ingolia NT, Lareau LF, Weissman JS. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell. 2011;147:789–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Sabi R, Tuller T. Computational analysis of nascent peptides that induce ribosome stalling and their proteomic distribution in Saccharomyces cerevisiae. RNA. 2017;23:983–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhao T, Chen YM, Li Y, Wang J, Chen S, Gao N, et al. Disome-seq reveals widespread ribosome collisions that promote cotranslational protein folding. Genome Biol. 2021;22:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank all members in Hao Chen’s Lab for their help and advice in experimental design. We thank Prof. Ruilin Tian for sharing the CRISPRi/Cas9 library screening vectors and all kind suggestions. The authors would also like to acknowledge the technical support from Hua Li and Lin Lin at SUSTech CRFT. This work was supported by Center for Computational Science and Engineering at Southern University of Science and Technology.

Funding

This work was supported by National Key Research and Development Program of China (2022YFC2702705), National Natural Science Foundation of China (31971330 and 32170586 to HHM, 82272703 to JBC, 32170604 to HC) and the Lingang Laboratory (Grant No.LG-QS-202204-04 to JBC). This work was also supported by Shenzhen Science and Technology Program (20231120115406001 and JCYJ20230807153703008), Pearl River Recruitment Program of Talents (2021QN02Y122) and Department of Health of Guangdong Province (B2021032) to HC, Shenzhen Key Laboratory of Gene Regulation and Systems Biology (Grant No. ZDSYS20200811144002008) from Shenzhen Innovation Committee of Science and Technology and Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (ZYCXTD2023004).

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Author notes

  1. These authors contributed equally: Xiaoyan Shi, Yangyi Zhang, Yuci Wang, Jie Wang.

Authors and Affiliations

  1. Department of Human Cell Biology and Genetics, Joint Laboratory of Guangdong & Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine; Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Southern University of Science and Technology, Shenzhen, 518055, China

    Xiaoyan Shi, Yangyi Zhang, Yuci Wang, Ruiqi Wang, Minggang Xiong, Yanlan Cao & Hao Chen

  2. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Medical Epigenetics and Metabolism, Fudan University, Shanghai, 200032, China

    Jie Wang, Liyong Wang, Honghui Ma & Jiabin Cai

  3. Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, 610041, China

    Yang Gao

  4. College of Polymer Science and Engineering, Med-X Center for Materials, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China

    Yang Gao

  5. School of Biological Sciences, The University of Hong Kong, Hong Kong, SAR, China

    Minggang Xiong

  6. State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China

    Ningjing Ou

  7. Rice Research Institute, Guangdong Academy of Agricultural Sciences; Key Laboratory of Genetics and Breeding of High Quality Rice in Southern China (Co-construction by Ministry and Province), Guangzhou, 510640, China

    Qi Liu

  8. Shenzhen Ruipuxun Academy for Stem Cell & Regenerative Medicine, Shenzhen, China

    Honghui Ma

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HHM and HC designed and conceived the experiments. YYZ and XYS performed most of the experiments. JBC provided clinical samples. JW and LYW performed pathological analysis. RQW and YLC assisted in CRISPRi/Cas9 library screening. YG helped to prepare figures. MGX and NJO assisted in polysome profiling. YCW, QL, and HC analyzed the data. XYS and HC wrote the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Qi Liu, Honghui Ma, Jiabin Cai or Hao Chen.

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The authors declare no competing interests.

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The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Zhongshan Hospital Research Ethics Committee, and written informed consent was obtained from each patient. Animal experiments were approved by the Institutional Animal Care and Use Committees (IACUC) of SUSTech.

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Shi, X., Zhang, Y., Wang, Y. et al. The tRNA Gm18 methyltransferase TARBP1 promotes hepatocellular carcinoma progression via metabolic reprogramming of glutamine. Cell Death Differ 31, 1219–1234 (2024). https://doi.org/10.1038/s41418-024-01323-4

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