Role of RNA modifications in cancer (original) (raw)

• Roundtree, I. A., Evans, M. E., Pan, T. & He, C. Dynamic RNA modifications in gene expression regulation. Cell 169, 1187–1200 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Li, S. & Mason, C. E. The pivotal regulatory landscape of RNA modifications. Annu. Rev. Genomics Hum. Genet. 15, 127–150 (2014).
  Article CAS PubMed Google Scholar
• Zhang, J., Yang, P. L. & Gray, N. S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 9, 28–39 (2009).
  Article PubMed CAS Google Scholar
• Dor, Y. & Cedar, H. Principles of DNA methylation and their implications for biology and medicine. Lancet 392, 777–786 (2018).
  Article CAS PubMed Google Scholar
• Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).
  Article CAS PubMed Google Scholar
• Mohammad, H. P., Barbash, O. & Creasy, C. L. Targeting epigenetic modifications in cancer therapy: erasing the roadmap to cancer. Nat. Med. 25, 403–418 (2019).
  Article CAS PubMed Google Scholar
• Gebert, L. F. R. & MacRae, I. J. Regulation of microRNA function in animals. Nat. Rev. Mol. Cell Biol. 20, 21–37 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Yao, R.-W., Wang, Y. & Chen, L.-L. Cellular functions of long noncoding RNAs. Nat. Cell Biol. 21, 542–551 (2019).
  Article CAS PubMed Google Scholar
• Zhao, B. S., Roundtree, I. A. & He, C. Post-transcriptional gene regulation by mRNA modifications. Nat. Rev. Mol. Cell Biol. 18, 31–42 (2017).
  Article CAS PubMed Google Scholar
• Shelton, S. B., Reinsborough, C. & Xhemalce, B. Who watches the watchmen: roles of RNA modifications in the RNA interference pathway. PLoS Genet. 12, e1006139 (2016).
  Article PubMed PubMed Central CAS Google Scholar
• Esteller, M. & Pandolfi, P. P. The epitranscriptome of noncoding RNAs in cancer. Cancer Discov. 7, 359–368 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Helm, M. & Motorin, Y. Detecting RNA modifications in the epitranscriptome: predict and validate. Nat. Rev. Genet. 18, 275–291 (2017).
  Article CAS PubMed Google Scholar
• Shubert, C. Epitranscriptomics: RNA revisited. Science 364, 693–695 (2019).
  Google Scholar
• Desrosiers, R., Friderici, K. & Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl Acad. Sci. USA 71, 3971–3975 (1974).
  Article CAS PubMed PubMed Central Google Scholar
• Fazi, F. & Fatica, A. Interplay between N6-methyladenosine (m6A) and non-coding RNAs in cell development and cancer. Front. Cell Dev. Biol. 7, 116 (2019).
  Article PubMed PubMed Central Google Scholar
• Alarcón, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482–485 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Maden, B. E. H. Identification of the locations of the methyl groups in 18S ribosomal RNA from Xenopus laevis and man. J. Mol. Biol. 189, 681–699 (1986).
  Article CAS PubMed Google Scholar
• Maden, B. E. H. Locations of methyl groups in 28S rRNA of xenopus laevis and man: clustering in the conserved core of molecule. J. Mol. Biol. 201, 289–314 (1988).
  Article CAS PubMed Google Scholar
• Liu, J. et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 10, 93–95 (2014). In this study, the METTL3–METTL14 complex is identified as the main m 6 A writer in mammalian cells.
  Article CAS PubMed Google Scholar
• Pendleton, K. E. et al. The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell 169, 824–835.e14 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• van Tran, N. et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 47, 7719–7733 (2019).
  Article PubMed PubMed Central CAS Google Scholar
• Ma, H. et al. N6-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat. Chem. Biol. 15, 88–94 (2019).
  Article CAS PubMed Google Scholar
• Perry, R. P. & Kelley, D. E. Existence of methylated messenger RNA in mouse L cells. Cell 1, 37–42 (1974).
  Article CAS Google Scholar
• Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012). This important study maps for the first time m 6 A modifications on the transcriptome, highlighting the importance of this modification for mRNA regulation and starting the new field of epitranscriptomics.
  Article CAS PubMed Google Scholar
• Patil, D. P. et al. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Jia, G. et al. N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 7, 885–887 (2011). In this study, the first m 6 A eraser is identified. This highlights the dynamic nature of this modification on mRNA.
  Article CAS PubMed PubMed Central Google Scholar
• Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).
  Article CAS PubMed Google Scholar
• Mauer, J. et al. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 541, 371–375 (2017).
  Article CAS PubMed Google Scholar
• Liao, S., Sun, H. & Xu, C. YTH domain: a family of N6-methyladenosine (m6A) readers. Genomics Proteomics Bioinformatics 16, 99–107 (2018).
  Article PubMed PubMed Central Google Scholar
• Huang, H. et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 20, 285–295 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Alarcón, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Wu, R. et al. A novel m6A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res. 29, 23–41 (2019).
  Article CAS PubMed Google Scholar
• Wu, B. et al. Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat. Commun. 9, 420 (2018).
  Article PubMed PubMed Central CAS Google Scholar
• Sun, L. et al. RNA structure maps across mammalian cellular compartments. Nat. Struct. Mol. Biol. 26, 322–330 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Du, H. et al. YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nat. Commun. 7, 12626 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388–1399 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Vu, L. P. et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 23, 1369–1376 (2017). In this study, METTL3 is found to increase MYC translation and sustain the growth of AML cells.
  Article CAS PubMed PubMed Central Google Scholar
• Barbieri, I. et al. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature 552, 126–131 (2017). This study identifies METTL3 as a potential target in AML and identifies a function of this enzyme that is dependent on its recruitment to chromatin.
  Article CAS PubMed PubMed Central Google Scholar
• Weng, H. et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m6A modification. Cell Stem Cell 22, 191–205.e9 (2018).
  Article CAS PubMed Google Scholar
• Lin, S., Choe, J., Du, P., Triboulet, R. & Gregory, R. I. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol. Cell 62, 335–345 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, M. et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology 67, 2254–2270 (2018).
  Article CAS PubMed Google Scholar
• Lin, X. et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat. Commun. 10, 2065 (2019).
  Article PubMed PubMed Central CAS Google Scholar
• Ma, J. et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N 6-methyladenosine-dependent primary MicroRNA processing. Hepatology 65, 529–543 (2017).
  Article CAS PubMed Google Scholar
• Liu, J. et al. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat. Cell Biol. 20, 1074–1083 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Cui, Q. et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 18, 2622–2634 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Visvanathan, A. et al. Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37, 522–533 (2018).
  Article CAS PubMed Google Scholar
• Li, F. et al. N6-methyladenosine modulates nonsense-mediated mRNA decay in human glioblastoma. Cancer Res. 79, 5785–5798 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Brown, J. A., Kinzig, C. G., DeGregorio, S. J. & Steitz, J. A. Methyltransferase-like protein 16 binds the 3′-terminal triple helix of MALAT1 long noncoding RNA. Proc. Natl Acad. Sci. USA 113, 14013–14018 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, Y. & Ma, L. New insights into long non-coding RNA MALAT1 in cancer and metastasis. Cancers 11, E216 (2019).
  Article PubMed CAS Google Scholar
• Iles, M. M. et al. A variant in FTO shows association with melanoma risk not due to BMI. Nat. Genet. 45, 428–432 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, S. et al. m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat. Commun. 10, 2782 (2019).
  Article PubMed PubMed Central CAS Google Scholar
• Li, Z. et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell 31, 127–141 (2017). This article describes the discovery of the oncogenic function of the m 6 A demethylase FTO in AML.
  Article PubMed CAS Google Scholar
• Elkashef, S. M. et al. IDH mutation, competitive inhibition of FTO, and RNA methylation. Cancer Cell 31, 619–620 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Su, R. et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 172, 90–105.e23 (2018).
  Article CAS PubMed Google Scholar
• Huang, Y. et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell 35, 677–691.e10 (2019). This article describes the first small-molecule inhibitor of the m 6 A pathway, which demonstrates efficacy in mouse models of AML.
  Article CAS PubMed PubMed Central Google Scholar
• Mauer, J. et al. FTO controls reversible m6Am RNA methylation during snRNA biogenesis. Nat. Chem. Biol. 15, 340–347 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, S. et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31, 591–606.e6 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, C. et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc. Natl Acad. Sci. USA 113, E2047–E2056 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Tanabe, A. et al. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated. Cancer Lett. 376, 34–42 (2016).
  Article CAS PubMed Google Scholar
• Paris, J. et al. Targeting the RNA m6A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell 25, 137–148.e6 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Han, D. et al. Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells. Nature 566, 270–274 (2019). In this study, YTHDF1 is identified as a critical suppressor of antigen presentation in dendritic cells and its depletion could enhance the effect of immune checkpoint inhibitors in melanoma.
  Article CAS PubMed PubMed Central Google Scholar
• Degrauwe, N., Suvà, M.-L., Janiszewska, M., Riggi, N. & Stamenkovic, I. IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. Genes. Dev. 30, 2459–2474 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Weidensdorfer, D. et al. Control of c-myc mRNA stability by IGF2BP1-associated cytoplasmic RNPs. RNA 15, 104 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Müller, S. et al. IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner. Nucleic Acids Res. 47, 375–390 (2019).
  Article PubMed CAS Google Scholar
• Bohnsack, K., Höbartner, C. & Bohnsack, M. Eukaryotic 5-methylcytosine (m5C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes 10, 102 (2019).
  Article CAS PubMed Central Google Scholar
• Trixl, L. & Lusser, A. The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip. Rev. RNA 10, e1510 (2019).
  Article PubMed CAS Google Scholar
• Schosserer, M. et al. Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan. Nat. Commun. 6, 6158 (2015).
  Article CAS PubMed Google Scholar
• Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Legrand, C. et al. Statistically robust methylation calling for whole-transcriptome bisulfite sequencing reveals distinct methylation patterns for mouse RNAs. Genome Res. 27, 1589–1596 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Song, C. X., Yi, C. & He, C. Mapping recently identified nucleotide variants in the genome and transcriptome. Nat. Biotechnol. 30, 1107–1116 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, T., Chen, W., Liu, J., Gu, N. & Zhang, R. Genome-wide identification of mRNA 5-methylcytosine in mammals. Nat. Struct. Mol. Biol. 26, 230–388 (2019). This study determines the abundance of high-confidence m 5 C modification sites within eukaryotic mRNAs.
  Article CAS Google Scholar
• Yang, X. et al. 5-methylcytosine promotes mRNA export — NSUN2 as the methyltransferase and ALYREF as an m5C reader. Cell Res. 27, 606–625 (2017). In this study, the first function of mRNA m 5 C and the first RNA m 5 C reader are identified.
  Article CAS PubMed PubMed Central Google Scholar
• Hussain, S. et al. NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep. 4, 255–261 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Freeman, J. W. et al. Identification and characterization of a human proliferation-associated nucleolar antigen with a molecular weight of 120,000 expressed in early G1 phase. Cancer Res. 48, 1244–1251 (1988).
  CAS PubMed Google Scholar
• Bantis, A. et al. Expression of p120, Ki-67 and PCNA as proliferation biomarkers in imprint smears of prostate carcinoma and their prognostic value. Cytopathology 15, 25–31 (2004).
  Article CAS PubMed Google Scholar
• Saijo, Y. et al. Expression of nucleolar protein p120 predicts poor prognosis in patients with stage I lung adenocarcinoma. Ann. Oncol. 12, 1121–1125 (2001).
  Article CAS PubMed Google Scholar
• Frye, M. & Watt, F. M. The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Curr. Biol. 16, 971–981 (2006). This article describes the discovery of NSUN2 as a MYC target and oncogenic factor.
  Article CAS PubMed Google Scholar
• Li, Y. et al. Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma. Cancer Lett. 430, 57–66 (2018).
  Article CAS PubMed Google Scholar
• Chen, X. et al. 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat. Cell Biol. 21, 978–990 (2019).
  Article CAS PubMed Google Scholar
• Campbell, T. M., Castro, M. A. A., de Oliveira, K. G., Ponder, B. A. J. & Meyer, K. B. ERα binding by transcription factors NFIB and YBX1 enables FGFR2 signaling to modulate estrogen responsiveness in breast cancer. Cancer Res. 78, 410–421 (2018).
  Article CAS PubMed Google Scholar
• Yamashita, T., Higashi, M., Momose, S., Morozumi, M. & Tamaru, J.-I. Nuclear expression of Y box binding-1 is important for resistance to chemotherapy including gemcitabine in TP53-mutated bladder cancer. Int. J. Oncol. 51, 579–586 (2017).
  Article CAS PubMed Google Scholar
• Cheng, J. X. et al. RNA cytosine methylation and methyltransferases mediate chromatin organization and 5-azacytidine response and resistance in leukaemia. Nat. Commun. 9, 1163 (2018).
  Article PubMed PubMed Central CAS Google Scholar
• Saikia, M., Fu, Y., Pavon-Eternod, M., He, C. & Pan, T. Genome-wide analysis of N1-methyl-adenosine modification in human tRNAs. RNA 16, 1317–1327 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Sloan, K. E. et al. Tuning the ribosome: the influence of rRNA modification on eukaryotic ribosome biogenesis and function. RNA Biol. 14, 1138–1152 (2017).
  Article PubMed Google Scholar
• Safra, M. et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251–255 (2017). This study presents the genome-wide mapping of m 1 A, showing limited abundance of this modification on mRNA.
  Article CAS PubMed Google Scholar
• Dominissini, D. et al. The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA. Nature 530, 441–446 (2016). This study presents the genome-wide mapping of m 1 A in mammalian cells, showing specific topology and association with high translation levels.
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, H. et al. Evolution of a reverse transcriptase to map N1-methyladenosine in human messenger RNA. Nat. Methods 16, 1281–1288 (2019). This study through the development of a new technique to detect m 1 A determines the topology of this modification on eukaryotic mRNAs.
  Article CAS PubMed PubMed Central Google Scholar
• Dai, X., Wang, T., Gonzalez, G. & Wang, Y. Identification of YTH domain-containing proteins as the readers for N 1-methyladenosine in RNA. Anal. Chem. 90, 6380–6384 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Z. et al. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 47, 2533–2545 (2019).
  Article CAS PubMed Google Scholar
• Liu, F. et al. ALKBH1-mediated trna demethylation regulates translation. Cell 167, 816–828.e16 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Woo, H.-H. & Chambers, S. K. Human ALKBH3-induced m1A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells. Biochim. Biophys. Acta Gene Regul. Mech. 1862, 35–46 (2019).
  Article CAS PubMed Google Scholar
• Konishi, N. et al. High expression of a new marker PCA-1 in human prostate carcinoma. Clin. Cancer Res. 11, 5090–5097 (2005).
  Article CAS PubMed Google Scholar
• Nakao, S. et al. Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs. Bioorg. Med. Chem. Lett. 24, 1071–1074 (2014).
  Article CAS PubMed Google Scholar
• Duncan, T. et al. Reversal of DNA alkylation damage by two human dioxygenases. Proc. Natl Acad. Sci. USA 99, 16660–16665 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Ramanathan, A., Robb, G. B. & Chan, S.-H. mRNA capping: biological functions and applications. Nucleic Acids Res. 44, 7511–7526 (2016).
  Article PubMed PubMed Central Google Scholar
• Tomikawa, C. 7-Methylguanosine modifications in transfer RNA (tRNA). Int. J. Mol. Sci. 19, E4080 (2018).
  Article PubMed Google Scholar
• Pandolfini, L. et al. METTL1 promotes let-7 microRNA processing via m7G methylation. Mol. Cell 74, 1278–1290.e9 (2019). In this study, internal m 7 G is identified on mature and pre-miRNAs, including let-7 , where it is required for pre- let-7 processing.
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, L. S. et al. Transcriptome-wide mapping of internal N7-methylguanosine methylome in mammalian mRNA. Mol. Cell 74, 1304–1316.e8 (2019). This article identifies internal m 7 G on mRNA and describes the transcriptome-wide mapping of the modification.
  Article CAS PubMed PubMed Central Google Scholar
• Alexandrov, A., Martzen, M. R. & Phizicky, E. M. Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA. RNA 8, 1253–1266 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Haag, S., Kretschmer, J. & Bohnsack, M. T. WBSCR22/Merm1 is required for late nuclear pre-ribosomal RNA processing and mediates N7-methylation of G1639 in human 18S rRNA. RNA 21, 180–187 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Malbec, L. et al. Dynamic methylome of internal mRNA N7-methylguanosine and its regulatory role in translation. Cell Res. 29, 927–941 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Cartlidge, R. A. et al. The tRNA methylase METTL1 is phosphorylated and inactivated by PKB and RSK in vitro and in cells. EMBO J. 24, 1696–1705 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Ping, Y. et al. Identifying core gene modules in glioblastoma based on multilayer factor-mediated dysfunctional regulatory networks through integrating multi-dimensional genomic data. Nucleic Acids Res. 43, 1997–2007 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Tian, Q.-H. et al. METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN. J. Mol. Med. 97, 1535–1545 (2019).
  Article CAS PubMed Google Scholar
• Okamoto, M. et al. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells. PLoS Genet. 10, e1004639 (2014).
  Article PubMed PubMed Central CAS Google Scholar
• Gustavsson, M. & Ronne, H. Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast. RNA 14, 666–674 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Tsukamoto, T., Shibagaki, Y., Niikura, Y. & Mizumoto, K. Cloning and characterization of three human cDNAs encoding mRNA (guanine-7-)-methyltransferase, an mRNA cap methylase. Biochem. Biophys. Res. Commun. 251, 27–34 (1998).
  Article CAS PubMed Google Scholar
• Posternak, V., Ung, M. H., Cheng, C. & Cole, M. D. MYC mediates mRNA cap methylation of canonical Wnt/β-catenin signaling transcripts by recruiting CDK7 and RNA methyltransferase. Mol. Cancer Res. 15, 213–224 (2017).
  Article CAS PubMed Google Scholar
• Franke, J., Gehlen, J. & Ehrenhofer-Murray, A. E. Hypermethylation of yeast telomerase RNA by the snRNA and snoRNA methyltransferase Tgs1. J. Cell Sci. 121, 3553–3560 (2008).
  Article CAS PubMed Google Scholar
• Shelton, S. B. et al. Crosstalk between the RNA methylation and histone-binding activities of MePCE regulates P-TEFb activation on chromatin. Cell Rep. 22, 1374–1383 (2018).
  Article CAS PubMed Google Scholar
• Singh, R. & Reddy, R. Gamma-monomethyl phosphate: a cap structure in spliceosomal U6 small nuclear RNA. Proc. Natl Acad. Sci. USA 86, 8280–8283 (1989).
  Article CAS PubMed PubMed Central Google Scholar
• Xhemalce, B., Robson, S. C. & Kouzarides, T. Human RNA methyltransferase BCDIN3D regulates microRNA processing. Cell 151, 278–288 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Martinez, A. et al. Human BCDIN3D monomethylates cytoplasmic histidine transfer RNA. Nucleic Acids Res. 45, 5423–5436 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Davis, F. F. & Allen, F. W. Ribonucleic acids from yeast which contain a fifth nucleotide. J. Biol. Chem. 227, 907–915 (1957).
  CAS PubMed Google Scholar
• Penzo, M., Guerrieri, A. N., Zacchini, F., Treré, D. & Montanaro, L. RNA pseudouridylation in physiology and medicine: for better and for worse. Genes 8, E301 (2017).
  Article PubMed CAS Google Scholar
• Carlile, T. M. et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature 515, 143–146 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Schwartz, S. et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148–162 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Li, X. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat. Chem. Biol. 11, 592–597 (2015). This article describes the transcriptome-wide mapping of pseudouridines in human cells.
  Article CAS PubMed Google Scholar
• Penzo, M. & Montanaro, L. Turning uridines around: role of rRNA pseudouridylation in ribosome biogenesis and ribosomal function. Biomolecules 8, E38 (2018).
  Article PubMed CAS Google Scholar
• Bohnsack, M. T. & Sloan, K. E. Modifications in small nuclear RNAs and their roles in spliceosome assembly and function. Biol. Chem. 399, 1265–1276 (2018).
  Article CAS PubMed Google Scholar
• Chen, J.-L., Opperman, K. K. & Greider, C. W. A critical stem-loop structure in the CR4-CR5 domain of mammalian telomerase RNA. Nucleic Acids Res. 30, 592–597 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Carlile, T. M. et al. mRNA structure determines modification by pseudouridine synthase 1. Nat. Chem. Biol. 15, 966–974 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, X. et al. Regulation of nuclear receptor activity by a pseudouridine synthase through posttranscriptional modification of steroid receptor RNA activator. Mol. Cell 15, 549–558 (2004).
  Article CAS PubMed Google Scholar
• Jana, S., Hsieh, A. C. & Gupta, R. Reciprocal amplification of caspase-3 activity by nuclear export of a putative human RNA-modifying protein, PUS10 during TRAIL-induced apoptosis. Cell Death Dis. 8, e3093–e3093 (2017).
  Article PubMed PubMed Central Google Scholar
• Heiss, N. S. et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat. Genet. 19, 32–38 (1998).
  Article CAS PubMed Google Scholar
• Ruggero, D. et al. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 299, 259–262 (2003). This study characterizes DKC1 as a tumour suppressor in a mouse model of dyskeratosis congenita, showing that the oncogenic effect of DKC1 loss-of-function mutations is caused by a lack of pseudouridylation of rRNA.
  Article CAS PubMed Google Scholar
• Montanaro, L. et al. Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation. Cancer Res. 70, 4767–4777 (2010).
  Article CAS PubMed Google Scholar
• Sieron, P. et al. DKC1 overexpression associated with prostate cancer progression. Br. J. Cancer 101, 1410 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Penzo, M. et al. Dyskerin and TERC expression may condition survival in lung cancer patients. Oncotarget 6, 21755–21760 (2015).
  Article PubMed PubMed Central Google Scholar
• Menezes, M. R., Balzeau, J. & Hagan, J. P. 3′ RNA uridylation in epitranscriptomics, gene regulation, and disease. Front. Mol. Biosci. 5, 61 (2018).
  Article PubMed PubMed Central CAS Google Scholar
• Martin, G. & Keller, W. RNA-specific ribonucleotidyl transferases. RNA 13, 1834–1849 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, C. et al. Star-PAP, a poly(A) polymerase, functions as a tumor suppressor in an orthotopic human breast cancer model. Cell Death Dis. 8, e2582–e2582 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Zhu, D., Lou, Y., He, Z. & Ji, M. Nucleotidyl transferase TUT1 inhibits lipogenesis in osteosarcoma cells through regulation of microRNA-24 and microRNA-29a. Tumor Biol. 35, 11829–11835 (2014).
  Article CAS Google Scholar
• Lim, J. et al. Uridylation by TUT4 and TUT7 marks mRNA for degradation. Cell 159, 1365–1376 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Heo, I. et al. Mono-uridylation of pre-microRNA as a key step in the biogenesis of group II let-7 microRNAs. Cell 151, 521–532 (2012).
  Article CAS PubMed Google Scholar
• Thornton, J. E., Chang, H.-M., Piskounova, E. & Gregory, R. I. Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7). RNA 18, 1875–1885 (2012). In this study, the LIN28-dependent uridylation of let-7 mediated by TUT4 and TUT7 and its effect on let-7 expression levels is discovered.
  Article CAS PubMed PubMed Central Google Scholar
• Wei, T. & Zhao, W.-X. The Wnt-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion. Artic. J. Cell Sci. 126, 2877–2889 (2013).
  Article CAS Google Scholar
• Alajez, N. M. et al. Lin28b promotes head and neck cancer progression via modulation of the insulin-like growth factor survival pathway. Oncotarget 3, 1641–1652 (2012).
  Article PubMed PubMed Central Google Scholar
• Balzeau, J., Menezes, M. R., Cao, S. & Hagan, J. P. The LIN28/let-7 pathway in cancer. Front. Genet. 8, 31 (2017).
  Article PubMed PubMed Central CAS Google Scholar
• Lin, S. & Gregory, R. I. Identification of small molecule inhibitors of Zcchc11 TUTase activity. RNA Biol. 12, 792–800 (2015).
  Article PubMed PubMed Central Google Scholar
• Chang, H.-M., Triboulet, R., Thornton, J. E. & Gregory, R. I. A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway. Nature 497, 244–248 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Astuti, D. et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat. Genet. 44, 277–284 (2012).
  Article CAS PubMed Google Scholar
• Ustianenko, D. et al. Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNAs. RNA 19, 1632–1638 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Hunter, R. W. et al. Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells. Genes. Dev. 32, 903–908 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, S. et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science 238, 363–366 (1987).
  Article CAS PubMed Google Scholar
• Powell, L. M. et al. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell 50, 831–840 (1987).
  Article CAS PubMed Google Scholar
• Rebagliati, M. R. & Melton, D. A. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 48, 599–605 (1987).
  Article CAS PubMed Google Scholar
• Bass, B. L. & Weintraub, H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 55, 1089–1098 (1988).
  Article CAS PubMed Google Scholar
• Bass, B. L. & Weintraub, H. A developmentally regulated activity that unwinds RNA duplexes. Cell 48, 607–613 (1987).
  Article CAS PubMed Google Scholar
• Nishikura, K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).
  Article CAS PubMed Google Scholar
• Herbert, A. ADAR and immune silencing in cancer. Trends Cancer 5, 272–282 (2019).
  Article CAS PubMed Google Scholar
• Chung, H. et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell 172, 811–824.e14 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Ishizuka, J. J. et al. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565, 43–48 (2019). In this study, ADAR1 depletion is shown to sensitize cells to immunotherapy and to prevent resistance, indicating that ADAR1 inhibition is a viable strategy to increase the efficacy of immunotherapies.
  Article CAS PubMed Google Scholar
• Weiss, S. A., Wolchok, J. D. & Sznol, M. Immunotherapy of melanoma: facts and hopes. Clin. Cancer Res. 25, 5191–5201 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Doroshow, D. B. et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin. Cancer Res. 25, 4592–4602 (2019).
  Article PubMed PubMed Central Google Scholar
• Adams, S. et al. Current landscape of immunotherapy in breast cancer: a review. JAMA Oncol. 5, 1205–1214 (2019).
  Article PubMed PubMed Central Google Scholar
• Chen, L. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209–216 (2013).
  Article PubMed PubMed Central CAS Google Scholar
• Okugawa, Y. et al. Enhanced AZIN1 RNA editing and overexpression of its regulatory enzyme ADAR1 are important prognostic biomarkers in gastric cancer. J. Transl Med. 16, 366 (2018).
  Article CAS PubMed PubMed Central Google Scholar
• Shigeyasu, K. et al. AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. JCI Insight 3, 99976 (2018).
  Article PubMed Google Scholar
• Chen, W. et al. A-to-I RNA editing of BLCAP lost the inhibition to STAT3 activation in cervical cancer. Oncotarget 8, 39417–39429 (2017).
  Article PubMed PubMed Central Google Scholar
• Lazzari, E. et al. Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat. Commun. 8, 1922 (2017).
  Article PubMed PubMed Central CAS Google Scholar
• Amin, E. M. et al. The RNA-editing enzyme ADAR promotes lung adenocarcinoma migration and invasion by stabilizing FAK. Sci. Signal. 10, eaah3941 (2017).
  Article PubMed PubMed Central CAS Google Scholar
• Zipeto, M. A. et al. ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell 19, 177–191 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Shoshan, E. et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17, 311–321 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, M. et al. RNA editing derived epitopes function as cancer antigens to elicit immune responses. Nat. Commun. 9, 3919 (2018).
  Article PubMed PubMed Central CAS Google Scholar
• Galeano, F. et al. ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene 32, 998–1009 (2013).
  Article CAS PubMed Google Scholar
• Tomaselli, S. et al. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol. 16, 5 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Wang, C. et al. Characterizing the role of PCDH9 in the regulation of glioma cell apoptosis and invasion. J. Mol. Neurosci. 52, 250–260 (2014).
  Article CAS PubMed Google Scholar
• Cesarini, V. et al. ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion. Nucleic Acids Res. 46, 2045–2059 (2018).
  Article CAS PubMed Google Scholar
• Kodama, T. et al. ADAM12 is selectively overexpressed in human glioblastomas and is associated with glioblastoma cell proliferation and shedding of heparin-binding epidermal growth factor. Am. J. Pathol. 165, 1743–1753 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Y. et al. ADAR3 expression is an independent prognostic factor in lower-grade diffuse gliomas and positively correlated with the editing level of GRIA2Q607R. Cancer Cell Int. 18, 196 (2018).
  Article PubMed PubMed Central CAS Google Scholar
• Fu, L. et al. RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer. Proc. Natl Acad. Sci. USA 114, E4631–E4640 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Y.-B. et al. ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma. Int. J. Oncol. 50, 622–630 (2017).
  Article CAS PubMed Google Scholar
• Deng, W. et al. Trm9-catalyzed tRNA modifications regulate global protein expression by codon-biased translation. PLoS Genet. 11, e1005706 (2015).
  Article PubMed PubMed Central CAS Google Scholar
• Nedialkova, D. D. & Leidel, S. A. Optimization of codon translation rates via tRNA modifications maintains proteome integrity. Cell 161, 1606–1618 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Rapino, F., Delaunay, S., Zhou, Z., Chariot, A. & Close, P. tRNA modification: is cancer having a wobble? Trends Cancer 3, 249–252 (2017).
  Article CAS PubMed Google Scholar
• Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558, 605–609 (2018). In this study, it is shown that U34 wobble-modifying enzymes are highly expressed in BRAF V600E -driven melanomas and their inhibition can restore sensitivity to BRAF inhibition in BRAF inhibitor-resistant melanomas.
  Article CAS PubMed Google Scholar
• Delaunay, S. et al. Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer. J. Exp. Med. 213, 2503–2523 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, A. et al. Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking ErbB2 (her-2/neu) overexpression. Int. J. Oncol. 27, 949–956 (2005).
  CAS PubMed Google Scholar
• Ladang, A. et al. Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine. J. Exp. Med. 212, 2057–2075 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Schapira, M. Structural chemistry of human RNA methyltransferases. ACS Chem. Biol. 11, 575–582 (2016).
  Article CAS PubMed Google Scholar
• Wang, P., Doxtader, K. A. & Nam, Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol. Cell 63, 306–317 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Pugh, C. S., Borchardt, R. T. & Stone, H. O. Sinefungin, a potent inhibitor of virion mRNA(guanine-7-)-methyltransferase, mRNA(nucleoside-2’-)-methyltransferase, and viral multiplication. J. Biol. Chem. 253, 4075–4077 (1978).
  CAS PubMed Google Scholar
• Stein, E. M. et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood 131, 2662–2669 (2018).
  Google Scholar
• Wang, L. et al. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth. Nat. Commun. 4, 2035 (2013).
  Article PubMed CAS Google Scholar
• Hashizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394–1396 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Véliz, E. A., Easterwood, L. H. M. & Beal, P. A. Substrate analogues for an RNA-editing adenosine deaminase: mechanistic investigation and inhibitor design. J. Am. Chem. Soc. 125, 10867–10876 (2003).
  Article PubMed CAS Google Scholar
• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  Article CAS PubMed Google Scholar
• Wolpaw, A. J. & Dang, C. V. Exploiting metabolic vulnerabilities of cancer with precision and accuracy. Trends Cell Biol. 28, 201–212 (2018).
  Article CAS PubMed Google Scholar
• Rizos, H. et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin. Cancer Res. 20, 1965–1977 (2014).
  Article CAS PubMed Google Scholar
• Keith, G. Mobilities of modified ribonucleotides on two-dimensional cellulose thin-layer chromatography. Biochimie 77, 142–144 (1995).
  Article CAS PubMed Google Scholar
• Liu, N. et al. Probing N6-methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA 19, 1848–1856 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Wetzel, C. & Limbach, P. A. Mass spectrometry of modified RNAs: recent developments. Analyst 141, 16–23 (2016).
  Article CAS PubMed Google Scholar
• Suzuki, T., Ueda, H., Okada, S. & Sakurai, M. Transcriptome-wide identification of adenosine-to-inosine editing using the ICE-seq method. Nat. Protoc. 10, 715–732 (2015).
  Article CAS PubMed Google Scholar
• Motorin, Y., Muller, S., Behm-Ansmant, I. & Branlant, C. Identification of modified residues in RNAs by reverse transcription-based methods. Methods Enzymol. 425, 21–53 (2007).
  Article CAS PubMed Google Scholar
• Edelheit, S., Schwartz, S., Mumbach, M. R., Wurtzel, O. & Sorek, R. Transcriptome-wide mapping of 5-methylcytidine RNA modifications in bacteria, archaea, and yeast reveals m5C within archaeal mRNAs. PLoS Genet. 9, e1003602 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Linder, B. et al. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods 12, 767–772 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Meyer, K. D. DART-seq: an antibody-free method for global m6A detection. Nat. Methods 16, 1275–1280 (2019).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, Z. et al. Single-base mapping of m6A by an antibody-independent method. Sci. Adv. 5, eaax0250 (2019).
  Article PubMed PubMed Central Google Scholar