RNA-modifying proteins as anticancer drug targets

Abstract

All major biological macromolecules (DNA, RNA, proteins and lipids) undergo enzyme-catalysed covalent modifications that impact their structure, function and stability. A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA stability and translation to proteins; these mechanisms of translational control have been termed epitranscriptomics. Emerging data suggest that some epitranscriptomic mechanisms are altered in human cancers as well as other human diseases. In this Review, we examine the current understanding of RNA modifications with a focus on mRNA methylation, highlight their possible roles in specific cancer indications and discuss the emerging potential of RNA-modifying proteins as therapeutic targets.

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Figure 1: Some examples of RNA nucleoside modifications found in Eukaryota.
Figure 2: Location and types of predominant RNA modification in mRNA and tRNA.
Figure 3: Selected structures of human RNA methyltransferases.
Figure 4: Overlays of ALKBH demethylases and RNA reader domains.

References

  1. 1

    Walsh, G. & Jefferis, R. Post-translational modifications in the context of therapeutic proteins. Nat. Biotechnol. 24, 1241–1252 (2006).

    CAS  PubMed  Google Scholar 

  2. 2

    Copeland, R. A., Solomon, M. E. & Richon, V. M. Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 8, 724–732 (2009).

    CAS  PubMed  Google Scholar 

  3. 3

    Ribich, S., Harvey, D. & Copeland, R. A. Drug discovery and chemical biology of cancer epigenetics. Cell Chem. Biol. 24, 1120–1147 (2017).

    CAS  PubMed  Google Scholar 

  4. 4

    Harlen, K. M. & Churchman, L. S. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat. Rev. Mol. Cell Biol. 18, 263–273 (2017).

    CAS  PubMed  Google Scholar 

  5. 5

    Filtz, T. M., Vogel, W. K. & Leid, M. Regulation of transcription factor activity by interconnected post-translational modifications. Trends Pharmacol. Sci. 35, 76–85 (2014).

    CAS  PubMed  Google Scholar 

  6. 6

    Gross, S., Rahal, R., Stransky, N., Lengauer, C. & Hoeflich, K. P. Targeting cancer with kinase inhibitors. J. Clin. Invest. 125, 1780–1789 (2015).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Saletore, Y. et al. The birth of the Epitranscriptome: deciphering the function of RNA modifications. Genome Biol. 13, 175 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Gilbert, W. V., Bell, T. A. & Schaening, C. Messenger RNA modifications: form, distribution, and function. Science 352, 1408–1412 (2016). This article provides a contemporary summary of RNA modifications and their impact on biology.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Peer, E., Rechavi, G. & Dominissini, D. Epitranscriptomics: regulation of mRNA metabolism through modifications. Curr. Opin. Chem. Biol. 41, 93–98 (2017).

    CAS  PubMed  Google Scholar 

  10. 10

    Roundtree, I. A., Evans, M. E., Pan, T. & He, C. Dynamic RNA modifications in gene expression regulation. Cell 169, 1187–1200 (2017). This paper is a good summary of dynamic modifications to coding RNAs and ncRNAs and their role in the development and regulation of genetic information.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Lewis, C. J., Pan, T. & Kalsotra, A. RNA modifications and structures cooperate to guide RNA-protein interactions. Nat. Rev. Mol. Cell Biol. 18, 202–210 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Zamir, A., Holley, R. W. & Marquisee, M. Evidence for the occurrence of a common pentanucleotide sequence in the structures of transfer ribonucleic acids. J. Biol. Chem. 240, 1267–1273 (1965).

    CAS  PubMed  Google Scholar 

  13. 13

    Singh, H. & Lane, B. G. The alkali-stable dinucleotide sequences in 18s+28s ribonucleates from wheat germ. Can. J. Biochem. 42, 1011–1021 (1964).

    CAS  PubMed  Google Scholar 

  14. 14

    Krol, A., Branlant, C., Lazar, E., Gallinaro, H. & Jacob, M. Primary and secondary structures of chicken, rat and man nuclear U4 RNAs. Homologies with U1 and U5 RNAs. Nucleic Acids Res. 9, 2699–2716 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Linder, B. et al. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods 12, 767–772 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Alarcon, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Zhou, C. et al. Genome-wide maps of m6A circRNAs identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs. Cell Rep. 20, 2262–2276 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Patil, D. P., Pickering, B. F. & Jaffrey, S. R. Reading m6A in the transcriptome: m6A-binding proteins. Trends Cell Biol. 28, 113–127 (2018).

    CAS  PubMed  Google Scholar 

  19. 19

    Barnash, K. D., James, L. I. & Frye, S. V. Target class drug discovery. Nat. Chem. Biol. 13, 1053–1056 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Machnicka, M. A. et al. MODOMICS: a database of RNA modification pathways—2013 update. Nucleic Acids Res. 41, D262–D267 (2013). This study generates a comprehensive database listing all known RNA modifications and the enzymes that facilitate these reactions.

    CAS  PubMed  Google Scholar 

  21. 21

    Zhang, C. et al. Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217- and ALKBH5-mediated modulation of RNA methylation in breast cancer cells. Oncotarget 7, 64527–64542 (2016).

    PubMed  PubMed Central  Google Scholar 

  22. 22

    Harcourt, E. M., Kietrys, A. M. & Kool, E. T. Chemical and structural effects of base modifications in messenger RNA. Nature 541, 339–346 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Edupuganti, R. R. et al. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat. Struct. Mol. Biol. 24, 870–878 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Karijolich, J., Yi, C. & Yu, Y. T. Transcriptome-wide dynamics of RNA pseudouridylation. Nat. Rev. Mol. Cell Biol. 16, 581–585 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Rintala-Dempsey, A. C. & Kothe, U. Eukaryotic stand-alone pseudouridine synthases — RNA modifying enzymes and emerging regulators of gene expression? RNA Biol. 14, 1185–1196 (2017).

    PubMed  PubMed Central  Google Scholar 

  26. 26

    Gallo, A., Vukic, D., Michalik, D., O'Connell, M. A. & Keegan, L. P. ADAR RNA editing in human disease; more to it than meets the I. Hum. Genet. 136, 1265–1278 (2017).

    CAS  PubMed  Google Scholar 

  27. 27

    Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).

    CAS  PubMed  Google Scholar 

  28. 28

    Schubert, H. L., Blumenthal, R. M. & Cheng, X. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem. Sci. 28, 329–335 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Yan, F. & Fujimori, D. G. RNA methylation by radical SAM enzymes RlmN and Cfr proceeds via methylene transfer and hydride shift. Proc. Natl Acad. Sci. USA 108, 3930–3934 (2011).

    CAS  PubMed  Google Scholar 

  30. 30

    Swinehart, W. E. & Jackman, J. E. Diversity in mechanism and function of tRNA methyltransferases. RNA Biol. 12, 398–411 (2015). This article provides a comprehensive review of the mechanisms of tRNA modification.

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Aravind, L. & Koonin, E. V. The DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate- and iron-dependent dioxygenases. Genome Biol. 2, research0007.1–research0007.8 (2001).

    Google Scholar 

  32. 32

    Rose, N. R., McDonough, M. A., King, O. N., Kawamura, A. & Schofield, C. J. Inhibition of 2-oxoglutarate dependent oxygenases. Chem. Soc. Rev. 40, 4364–4397 (2011).

    CAS  PubMed  Google Scholar 

  33. 33

    Fedeles, B. I., Singh, V., Delaney, J. C., Li, D. & Essigmann, J. M. The AlkB family of Fe(II)/alpha-ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J. Biol. Chem. 290, 20734–20742 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Alemu, E. A., He, C. & Klungland, A. ALKBHs-facilitated RNA modifications and de-modifications. DNA Repair (Amst.) 44, 87–91 (2016).

    Google Scholar 

  35. 35

    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). This paper presents the identification of the obesity-associated FTO enzyme as an m6A RNA demethylase.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).

    CAS  PubMed  Google Scholar 

  37. 37

    Mauer, J. et al. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 541, 371–375 (2017).

    CAS  PubMed  Google Scholar 

  38. 38

    Zhu, Y. et al. LC-MS-MS quantitative analysis reveals the association between FTO and DNA methylation. PLoS ONE 12, e0175849 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. 39

    van den Born, E. et al. ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA. Nat. Commun. 2, 172 (2011).

    PubMed  Google Scholar 

  40. 40

    Fu, Y. et al. The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA. Angew. Chem. Int. Ed Engl. 49, 8885–8888 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Ergel, B. et al. Protein dynamics control the progression and efficiency of the catalytic reaction cycle of the Escherichia coli DNA-repair enzyme AlkB. J. Biol. Chem. 289, 29584–29601 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Stoilov, P., Rafalska, I. & Stamm, S. YTH: a new domain in nuclear proteins. Trends Biochem. Sci. 27, 495–497 (2002).

    CAS  PubMed  Google Scholar 

  44. 44

    Zhang, Z. et al. The YTH domain is a novel RNA binding domain. J. Biol. Chem. 285, 14701–14710 (2010).

    CAS  PubMed  Google Scholar 

  45. 45

    Xu, C. et al. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat. Chem. Biol. 10, 927–929 (2014). This study identifies an RNA-binding motif required for m6A readers.

    CAS  Google Scholar 

  46. 46

    Wang, X. et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505, 117–120 (2014). This study characterizes the role of m6A in RNA half-life and degradation.

    PubMed  Google Scholar 

  47. 47

    Schwartz, S. et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 8, 284–296 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Liu, N. et al. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 45, 6051–6063 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Monecke, T., Dickmanns, A. & Ficner, R. Structural basis for m7G-cap hypermethylation of small nuclear, small nucleolar and telomerase RNA by the dimethyltransferase TGS1. Nucleic Acids Res. 37, 3865–3877 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Li, X., Xiong, X. & Yi, C. Epitranscriptome sequencing technologies: decoding RNA modifications. Nat. Methods 14, 23–31 (2016).

    PubMed  Google Scholar 

  53. 53

    Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Ke, S. et al. A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation. Genes Dev. 20, 2037–2053 (2015).

    Google Scholar 

  56. 56

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Xiao, W. et al. Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol. Cell 61, 507–519 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Zheng, Q., Hou, J., Zhou, Y., Li, Z. & Cao, X. The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus. Nat. Immunol. 18, 1094–1103 (2017).

    CAS  PubMed  Google Scholar 

  59. 59

    Fry, N. J., Law, B. A., Ilkayeva, O. R., Holley, C. L. & Mansfield, K. D. N6-methyladenosine is required for the hypoxic stabilization of specific mRNAs. RNA 23, 1444–1455 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Coots, R. A. et al. m6A facilitates eIF4F-independent mRNA translation. Mol. Cell 68, 504–514.e7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Patil, D. P. et al. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Zhang, C. et al. m6A modulates haematopoietic stem and progenitor cell specification. Nature 549, 273–276 (2017).

    CAS  PubMed  Google Scholar 

  64. 64

    Li, H. B. et al. m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548, 338–342 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Yoon, K. J. et al. Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell 171, 877–889.e17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014). This article presents the discovery that METTL3 and m6A are critical for appropriate cellular differentiation.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).

    CAS  PubMed  Google Scholar 

  68. 68

    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). This paper implicates the m6A methyltransferase METTL3 in the pathogenesis of AML.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Schwartz, S. et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 155, 1409–1421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Safra, M. et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251–255 (2017).

    CAS  PubMed  Google Scholar 

  71. 71

    Li, X. et al. Base-resolution mapping reveals distinct m1A methylome in nuclear- and mitochondrial-encoded transcripts. Mol. Cell 68, 993–1005.e9 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Motorin, Y., Lyko, F. & Helm, M. 5-Methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res. 38, 1415–1430 (2010).

    CAS  PubMed  Google Scholar 

  75. 75

    Li, X. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat. Chem. Biol. 11, 592–597 (2015).

    CAS  PubMed  Google Scholar 

  76. 76

    Agris, P. F. et al. Celebrating wobble decoding: half a century and still much is new. RNA Biol. https://doi.org/10.1080/15476286.2017.1356562 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. 77

    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 study implicates the m6A demethylase FTO in the pathogenesis of AML.

    Google Scholar 

  78. 78

    Su, R. et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 172, 90–105.e23 (2018).

    CAS  PubMed  Google Scholar 

  79. 79

    Barbieri, I. et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature 552, 126–131 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    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).

    CAS  PubMed  Google Scholar 

  81. 81

    Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. & Rich, J. N. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203–1217 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Cui, Q. et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 18, 2622–2634 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Visvanathan, A. et al. Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37, 522–533 (2018).

    CAS  PubMed  Google Scholar 

  85. 85

    Hsu, P. J., Shi, H. & He, C. Epitranscriptomic influences on development and disease. Genome Biol. 18, 197 (2017).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Ma, Z. et al. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute mega-karyoblastic leukemia. Nat. Genet. 28, 220–221 (2001).

    CAS  PubMed  Google Scholar 

  87. 87

    Tanabe, A. et al. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1alpha mRNA is translated. Cancer Lett. 376, 34–42 (2016).

    CAS  PubMed  Google Scholar 

  88. 88

    Goodarzi, H. et al. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell 165, 1416–1427 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Yu, Y. P. et al. Novel fusion transcripts associate with progressive prostate cancer. Am. J. Pathol. 184, 2840–2849 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Gatza, M. L., Silva, G. O., Parker, J. S., Fan, C. & Perou, C. M. An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat. Genet. 46, 1051–1059 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Frye, M. et al. Genomic gain of 5p15 leads to over-expression of Misu (NSUN2) in breast cancer. Cancer Lett. 289, 71–80 (2010).

    CAS  PubMed  Google Scholar 

  92. 92

    Okamoto, M. et al. Frequent increased gene copy number and high protein expression of tRNA (cytosine-5-)-methyltransferase (NSUN2) in human cancers. DNA Cell Biol. 31, 660–671 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Yi, J. et al. Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer. Oncotarget 8, 20751–20765 (2017).

    PubMed  Google Scholar 

  94. 94

    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).

    CAS  PubMed  Google Scholar 

  95. 95

    Hicks, D. G. et al. The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence. BMC Cancer 10, 108 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Bartlett, J. M. et al. Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy. Breast Cancer Res. 12, R47 (2010).

    PubMed  PubMed Central  Google Scholar 

  97. 97

    Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).

    CAS  PubMed  Google Scholar 

  99. 99

    Speakman, J. R. The 'fat mass and obesity related' (FTO) gene: mechanisms of impact on obesity and energy balance. Curr. Obes. Rep. 4, 73–91 (2015).

    PubMed  Google Scholar 

  100. 100

    Van Haute, L. et al. Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat. Commun. 7, 12039 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Metodiev, M. D. et al. Recessive mutations in TRMT10C cause defects in mitochondrial RNA processing and multiple respiratory chain deficiencies. Am. J. Hum. Genet. 98, 993–1000 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Martinez, F. J. et al. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J. Med. Genet. 49, 380–385 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Fahiminiya, S. et al. Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar. Clin. Genet. 86, 134–141 (2014).

    CAS  PubMed  Google Scholar 

  104. 104

    Doll, A. & Grzeschik, K. H. Characterization of two novel genes, WBSCR20 and WBSCR22, deleted in Williams-Beuren syndrome. Cytogenet. Cell Genet. 95, 20–27 (2001).

    CAS  PubMed  Google Scholar 

  105. 105

    Franke, B. et al. An association study of 45 folate-related genes in spina bifida: involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1). Birth Defects Res. A Clin. Mol. Teratol. 85, 216–226 (2009).

    CAS  PubMed  Google Scholar 

  106. 106

    Guy, M. P. et al. Defects in tRNA anticodon loop 2′-O-methylation are implicated in nonsyndromic X-linked intellectual disability due to mutations in FTSJ1. Hum. Mutat. 36, 1176–1187 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Lichinchi, G. et al. Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host Microbe 20, 666–673 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Gokhale, N. S. et al. N6-methyladenosine in flaviviridae viral RNA genomes regulates infection. Cell Host Microbe 20, 654–665 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Kennedy, E. M. et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 19, 675–685 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Lichinchi, G. et al. Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells. Nat. Microbiol. 1, 16011 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Jonkhout, N. et al. The RNA modification landscape in human disease. RNA 23, 1754–1769 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Torres, A. G., Batlle, E. & Ribas de Pouplana, L. Role of tRNA modifications in human diseases. Trends Mol. Med. 20, 306–314 (2014).

    CAS  PubMed  Google Scholar 

  113. 113

    Leelananda, S. P. & Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem. 12, 2694–2718 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Stephenson, R. C. & Clarke, S. Characterization of a rat liver protein carboxyl methyltransferase involved in the maturation of proteins with the -CXXX C-terminal sequence motif. J. Biol. Chem. 267, 13314–13319 (1992).

    CAS  PubMed  Google Scholar 

  115. 115

    Kaminska, K. H. et al. Insights into the structure, function and evolution of the radical-SAM 23S rRNA methyltransferase Cfr that confers antibiotic resistance in bacteria. Nucleic Acids Res. 38, 1652–1663 (2010).

    CAS  PubMed  Google Scholar 

  116. 116

    Kimura, S. et al. Discovery of the beta-barrel-type RNA methyltransferase responsible for N6-methylation of N6-threonylcarbamoyladenosine in tRNAs. Nucleic Acids Res. 42, 9350–9365 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Malone, T., Blumenthal, R. M. & Cheng, X. Structure-guided analysis reveals nine sequence motifs conserved among DNA amino-methyltransferases, and suggests a catalytic mechanism for these enzymes. J. Mol. Biol. 253, 618–632 (1995).

    CAS  PubMed  Google Scholar 

  118. 118

    Byszewska, M., Smietanski, M., Purta, E. & Bujnicki, J. M. RNA methyltransferases involved in 5′ cap biosynthesis. RNA Biol. 11, 1597–1607 (2014).

    PubMed  Google Scholar 

  119. 119

    Iyer, L. M., Zhang, D. & Aravind, L. Adenine methylation in eukaryotes: apprehending the complex evolutionary history and functional potential of an epigenetic modification. Bioessays 38, 27–40 (2016).

    CAS  PubMed  Google Scholar 

  120. 120

    Richon, V. M. et al. Chemogenetic analysis of human protein methyltransferases. Chem. Biol. Drug Des. 78, 199–210 (2011).

    CAS  PubMed  Google Scholar 

  121. 121

    Koonin, E. V. & Rudd, K. E. SpoU protein of Escherichia coli belongs to a new family of putative rRNA methylases. Nucleic Acids Res. 21, 5519 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Gustafsson, C., Reid, R., Greene, P. J. & Santi, D. V. Identification of new RNA modifying enzymes by iterative genome search using known modifying enzymes as probes. Nucleic Acids Res. 24, 3756–3762 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Nureki, O. et al. An enzyme with a deep trefoil knot for the active-site architecture. Acta Crystallogr. D Biol. Crystallogr. 58, 1129–1137 (2002).

    PubMed  Google Scholar 

  124. 124

    Michel, G. et al. The structure of the RlmB 23S rRNA methyltransferase reveals a new methyltransferase fold with a unique knot. Structure 10, 1303–1315 (2002).

    CAS  PubMed  Google Scholar 

  125. 125

    Schapira, M. Structural chemistry of human RNA methyltransferases. ACS Chem. Biol. 11, 575–582 (2016). This article provides a review and druggability analysis of RNMTs.

    CAS  PubMed  Google Scholar 

  126. 126

    Liu, L., Zhen, X. T., Denton, E., Marsden, B. D. & Schapira, M. ChromoHub: a data hub for navigators of chromatin-mediated signalling. Bioinformatics 28, 2205–2206 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Smietanski, M. et al. Structural analysis of human 2′-O-ribose methyltransferases involved in mRNA cap structure formation. Nat. Commun. 5, 3004 (2014).

    PubMed  PubMed Central  Google Scholar 

  128. 128

    Wang, X. et al. Structural basis of N6-adenosine methylation by the METTL3-METTL14 complex. Nature 534, 575–578 (2016).

    CAS  PubMed  Google Scholar 

  129. 129

    Wang, P., Doxtader, K. A. & Nam, Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol. Cell 63, 306–317 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Sledz, P. & Jinek, M. Structural insights into the molecular mechanism of the m6A writer complex. eLife 5, e18434 (2016).

    PubMed  PubMed Central  Google Scholar 

  131. 131

    Wu, B., Li, L., Huang, Y., Ma, J. & Min, J. Readers, writers and erasers of N6-methylated adenosine modification. Curr. Opin. Struct. Biol. 47, 67–76 (2017).

    PubMed  Google Scholar 

  132. 132

    Liu, R. J., Long, T., Li, J., Li, H. & Wang, E. D. Structural basis for substrate binding and catalytic mechanism of a human RNA:m5C methyltransferase NSun6. Nucleic Acids Res. 45, 6684–6697 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Finer-Moore, J., Czudnochowski, N., O'Connell, J. D. III, Wang, A. L. & Stroud, R. M. Crystal structure of the human tRNA m(1)A58 methyltransferase-tRNA(3)(Lys) complex: refolding of substrate tRNA allows access to the methylation target. J. Mol. Biol. 427, 3862–3876 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Boriack-Sjodin, P. A. & Swinger, K. K. Protein methyltransferases: a distinct, diverse, and dynamic family of enzymes. Biochemistry 55, 1557–1569 (2016).

    CAS  PubMed  Google Scholar 

  135. 135

    Kurowski, M. A., Bhagwat, A. S., Papaj, G. & Bujnicki, J. M. Phylogenomic identification of five new human homologs of the DNA repair enzyme AlkB. BMC Genomics 4, 48 (2003).

    PubMed  PubMed Central  Google Scholar 

  136. 136

    Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Sanchez-Pulido, L. & Andrade-Navarro, M. A. The FTO (fat mass and obesity associated) gene codes for a novel member of the non-heme dioxygenase superfamily. BMC Biochem. 8, 23 (2007).

    PubMed  PubMed Central  Google Scholar 

  138. 138

    Yu, B. et al. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB. Nature 439, 879–884 (2006).

    CAS  PubMed  Google Scholar 

  139. 139

    Sundheim, O. et al. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. EMBO J. 25, 3389–3397 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Yang, C. G. et al. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature 452, 961–965 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Lu, L., Yi, C., Jian, X., Zheng, G. & He, C. Structure determination of DNA methylation lesions N1-meA and N3-meC in duplex DNA using a cross-linked protein-DNA system. Nucleic Acids Res. 38, 4415–4425 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Yi, C. et al. Duplex interrogation by a direct DNA repair protein in search of base damage. Nat. Struct. Mol. Biol. 19, 671–676 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Chen, B., Gan, J. & Yang, C. G. The complex structures of ALKBH2 mutants cross-linked to dsDNA reveal the conformational swimg of β-haripin. Sci. China Chem. 57, 307–313 (2014).

    CAS  Google Scholar 

  144. 144

    Aik, W. et al. Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. Nucleic Acids Res. 42, 4741–4754 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Feng, C. et al. Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition. J. Biol. Chem. 289, 11571–11583 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Xu, C. et al. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. J. Biol. Chem. 289, 17299–17311 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Wang, G. et al. The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism. J. Biol. Chem. 289, 27924–27936 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Pastore, C. et al. Crystal structure and RNA binding properties of the RNA recognition motif (RRM) and AlkB domains in human AlkB homolog 8 (ABH8), an enzyme catalyzing tRNA hypermodification. J. Biol. Chem. 287, 2130–2143 (2012).

    CAS  PubMed  Google Scholar 

  149. 149

    Han, Z. et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464, 1205–1209 (2010).

    CAS  PubMed  Google Scholar 

  150. 150

    Toh, J. D. W. et al. A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO. Chem. Sci. 6, 112–122 (2015).

    CAS  PubMed  Google Scholar 

  151. 151

    Aik, W. et al. Structural basis for inhibition of the fat mass and obesity associated protein (FTO). J. Med. Chem. 56, 3680–3688 (2013).

    CAS  PubMed  Google Scholar 

  152. 152

    Huang, Y. et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 43, 373–384 (2015).

    CAS  PubMed  Google Scholar 

  153. 153

    Wang, T. et al. Fluorescein derivatives as bifunctional molecules for the simultaneous inhibiting and labeling of FTO protein. J. Am. Chem. Soc. 137, 13736–13739 (2015).

    CAS  PubMed  Google Scholar 

  154. 154

    He, W. et al. Identification of a novel small-molecule binding site of the fat mass and obesity associated protein (FTO). J. Med. Chem. 58, 7341–7348 (2015).

    CAS  PubMed  Google Scholar 

  155. 155

    Chen, Y. & Varani, G. Protein families and RNA recognition. FEBS J. 272, 2088–2097 (2005).

    CAS  PubMed  Google Scholar 

  156. 156

    Theler, D., Dominguez, C., Blatter, M., Boudet, J. & Allain, F. H. Solution structure of the YTH domain in complex with N6-methyladenosine RNA: a reader of methylated RNA. Nucleic Acids Res. 42, 13911–13919 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Luo, S. & Tong, L. Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain. Proc. Natl Acad. Sci. USA 111, 13834–13839 (2014).

    CAS  PubMed  Google Scholar 

  158. 158

    Zhu, T. et al. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res. 24, 1493–1496 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159

    Li, F., Zhao, D., Wu, J. & Shi, Y. Structure of the YTH domain of human YTHDF2 in complex with an m6A mononucleotide reveals an aromatic cage for m6A recognition. Cell Res. 24, 1490–1492 (2014).

    PubMed  PubMed Central  Google Scholar 

  160. 160

    Xu, C. et al. Structural basis for the discriminative recognition of N6-methyladenosine RNA by the human YT521-B homology domain family of proteins. J. Biol. Chem. 290, 24902–24913 (2015).

    CAS  PubMed  Google Scholar 

  161. 161

    Niedzwiecka, A. et al. Biophysical studies of eIF4E cap-binding protein: recognition of mRNA 5′ cap structure and synthetic fragments of eIF4G and 4E-BP1 proteins. J. Mol. Biol. 319, 615–635 (2002).

    CAS  PubMed  Google Scholar 

  162. 162

    Mazza, C., Segref, A., Mattaj, I. W. & Cusack, S. Large-scale induced fit recognition of an m7GpppG cap analogue by the human nuclear cap-binding complex. EMBO J. 21, 5548–5557 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Gu, M. et al. Insights into the structure, mechanism, and regulation of scavenger mRNA decapping activity. Mol. Cell 14, 67–80 (2004).

    CAS  PubMed  Google Scholar 

  164. 164

    Monecke, T., Schell, S., Dickmanns, A. & Ficner, R. Crystal structure of the RRM domain of poly(A)-specific ribonuclease reveals a novel m7G-cap-binding mode. J. Mol. Biol. 382, 827–834 (2008).

    CAS  PubMed  Google Scholar 

  165. 165

    Nagata, T. et al. The RRM domain of poly(A)-specific ribonuclease has a noncanonical binding site for mRNA cap analog recognition. Nucleic Acids Res. 36, 4754–4767 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Wu, M. et al. Structural basis of m7GpppG binding to poly(A)-specific ribonuclease. Structure 17, 276–286 (2009).

    CAS  PubMed  Google Scholar 

  167. 167

    Karaki, S., Andrieu, C., Ziouziou, H. & Rocchi, P. The eukaryotic translation initiation factor 4E (eIF4E) as a therapeutic target for cancer. Adv. Protein Chem. Struct. Biol. 101, 1–26 (2015).

    CAS  PubMed  Google Scholar 

  168. 168

    Chen, X. et al. Structure-guided design, synthesis, and evaluation of guanine-derived inhibitors of the eIF4E mRNA-cap interaction. J. Med. Chem. 55, 3837–3851 (2012).

    CAS  PubMed  Google Scholar 

  169. 169

    Soukarieh, F. et al. Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: synthesis, structural and functional characterisation. Eur. J. Med. Chem. 124, 200–217 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Gnyszka, A., Jastrzebski, Z. & Flis, S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 33, 2989–2996 (2013).

    CAS  PubMed  Google Scholar 

  171. 171

    Kaniskan, H. U., Martini, M. L. & Jin, J. Inhibitors of protein methyltransferases and demethylases. Chem. Rev. 118, 989–1068 (2018).

    CAS  PubMed  Google Scholar 

  172. 172

    Jambhekar, A., Anastas, J. N. & Shi, Y. Histone lysine demethylase inhibitors. Cold Spring Harb. Perspect. Med. 7, a026484 (2017).

    PubMed  PubMed Central  Google Scholar 

  173. 173

    Kim, S. Y. & Yang, E. G. Recent advances in developing inhibitors for hypoxia-inducible factor prolyl hydroxylases and their therapeutic implications. Molecules 20, 20551–20568 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    James, L. I. et al. Small-molecule ligands of methyl-lysine binding proteins: optimization of selectivity for L3MBTL3. J. Med. Chem. 56, 7358–7371 (2013).

    CAS  PubMed  Google Scholar 

  175. 175

    James, L. I. et al. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat. Chem. Biol. 9, 184–191 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Barnash, K. D. et al. Discovery of peptidomimetic ligands of EED as allosteric inhibitors of PRC2. ACS Comb. Sci. 19, 161–172 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177

    Qi, W. et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat. Chem. Biol. 13, 381–388 (2017).

    CAS  PubMed  Google Scholar 

  178. 178

    Li, L. et al. Discovery and molecular basis of a diverse set of polycomb repressive complex 2 inhibitors recognition by EED. PLoS ONE 12, e0169855 (2017).

    PubMed  PubMed Central  Google Scholar 

  179. 179

    Huang, Y. et al. Discovery of first-in-class, potent, and orally bioavailable embryonic ectoderm development (EED) inhibitor with robust anticancer efficacy. J. Med. Chem. 60, 2215–2226 (2017).

    CAS  PubMed  Google Scholar 

  180. 180

    Lingel, A. et al. Structure-guided design of EED binders allosterically inhibiting the epigenetic polycomb repressive complex 2 (PRC2) methyltransferase. J. Med. Chem. 60, 415–427 (2017).

    CAS  PubMed  Google Scholar 

  181. 181

    Curtin, M. L. et al. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. Bioorg. Med. Chem. Lett. 27, 1576–1583 (2017).

    CAS  PubMed  Google Scholar 

  182. 182

    He, Y. et al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol. 13, 389–395 (2017).

    CAS  PubMed  Google Scholar 

  183. 183

    Sanchez, R., Meslamani, J. & Zhou, M. M. The bromodomain: from epigenome reader to druggable target. Biochim. Biophys. Acta 1839, 676–685 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184

    Galdeano, C. Drugging the undruggable: targeting challenging E3 ligases for personalized medicine. Future Med. Chem. 9, 347–350 (2017).

    CAS  PubMed  Google Scholar 

  185. 185

    Arrowsmith, C. H. et al. The promise and peril of chemical probes. Nat. Chem. Biol. 11, 536–541 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186

    Copeland, R. A. & Boriack-Sjodin, P. A. The elements of translational chemical biology. Cell Chem. Biol. 25, 128–134 (2018).

    CAS  PubMed  Google Scholar 

  187. 187

    Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Disovery: A Guide for Medicinal Chemists and Pharmacologists 2nd edn (Wiley, 2013).

    Google Scholar 

  188. 188

    Boccaletto, P. et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 46, D303–D307 (2018).

    CAS  PubMed  Google Scholar 

  189. 189

    Tomoo, K. et al. Structural basis for mRNA Cap-Binding regulation of eukaryotic initiation factor 4E by 4E-binding protein, studied by spectroscopic, X-ray crystal structural, and molecular dynamics simulation methods. Biochim. Biophys. Acta 1753, 191–208 (2005).

    CAS  PubMed  Google Scholar 

  190. 190

    Rosettani, P., Knapp, S., Vismara, M. G., Rusconi, L. & Cameron, A. D. Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms. J. Mol. Biol. 368, 691–705 (2007).

    CAS  PubMed  Google Scholar 

  191. 191

    Chen, M. et al. RNA N6-methyladenosine methyltransferase METTL3 promotes liver cancer progression through YTHDF2 dependent post-transcriptional silencing of SOCS2. Hepatology https://doi.org/10.1002/hep.29683 (2017).

    CAS  PubMed  Google Scholar 

  192. 192

    Okamoto, M. et al. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells. PLoS Genet. 10, e1004639 (2014).

    PubMed  PubMed Central  Google Scholar 

  193. 193

    Zhang, Z. et al. METTL13 is downregulated in bladder carcinoma and suppresses cell proliferation, migration and invasion. Sci. Rep. 6, 19261 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194

    Yeon, S. Y. et al. Frameshift mutations in repeat sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 genes in colon cancers. Pathol. Oncol. Res. https://doi.org/10.1007/s12253-017-0287-2 (2017).

    Google Scholar 

  195. 195

    Job, B. et al. Genomic aberrations in lung adenocarcinoma in never smokers. PLoS ONE 5, e15145 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196

    Kar, S. P. et al. Genome-wide meta-analyses of breast, ovarian, and prostate cancer association studies identify multiple new susceptibility loci shared by at least two cancer types. Cancer Discov. 6, 1052–1067 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Rodriguez, V. et al. Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer. Genes Chromosomes Cancer 46, 694–707 (2007).

    CAS  PubMed  Google Scholar 

  198. 198

    Couch, F. J. et al. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nat. Commun. 7, 11375 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199

    Elhardt, W., Shanmugam, R., Jurkowski, T. P. & Jeltsch, A. Somatic cancer mutations in the DNMT2 tRNA methyltransferase alter its catalytic properties. Biochimie 112, 66–72 (2015).

    CAS  PubMed  Google Scholar 

  200. 200

    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).

    CAS  PubMed  Google Scholar 

  201. 201

    Yao, L. et al. Elevated expression of RNA methyltransferase BCDIN3D predicts poor prognosis in breast cancer. Oncotarget 7, 53895–53902 (2016).

    PubMed  PubMed Central  Google Scholar 

  202. 202

    Shimada, K. et al. A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. Cancer Res. 69, 3157–3164 (2009).

    CAS  PubMed  Google Scholar 

  203. 203

    Begley, U. et al. A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-alpha. EMBO Mol. Med. 5, 366–383 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Hoff, A. M. et al. Identification of novel fusion genes in testicular germ cell tumors. Cancer Res. 76, 108–116 (2016).

    CAS  PubMed  Google Scholar 

  205. 205

    Marcel, V. et al. p53 acts as a safeguard of translational control by regulating fibrillarin and rRNA methylation in cancer. Cancer Cell 24, 318–330 (2013).

    CAS  PubMed  Google Scholar 

  206. 206

    Su, H. et al. Elevated snoRNA biogenesis is essential in breast cancer. Oncogene 33, 1348–1358 (2014).

    CAS  PubMed  Google Scholar 

  207. 207

    Ikeda, S. et al. Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma. Cancer Sci. 108, 641–652 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208

    Ueda, Y. et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells. Sci. Rep. 7, 42271 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. 209

    Tan, A., Dang, Y., Chen, G. & Mo, Z. Overexpression of the fat mass and obesity associated gene (FTO) in breast cancer and its clinical implications. Int. J. Clin. Exp. Pathol. 8, 13405–13410 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Liu, Y. et al. The lipid metabolism gene FTO influences breast cancer cell energy metabolism via the PI3K/AKT signaling pathway. Oncol. Lett. 13, 4685–4690 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211

    Chen, J. et al. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle 16, 2259–2271 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 212

    Nguyen, T. T. et al. Identification of novel Runx1 (AML1) translocation partner genes SH3D19, YTHDf2, and ZNF687 in acute myeloid leukemia. Genes Chromosomes Cancer 45, 918–932 (2006).

    CAS  PubMed  Google Scholar 

  213. 213

    Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).

    CAS  PubMed  Google Scholar 

  214. 214

    Chowdhury, R. et al. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure 17, 981–989 (2009).

    CAS  PubMed  Google Scholar 

  215. 215

    Rose, N. R. et al. Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. J. Med. Chem. 51, 7053–7056 (2008).

    CAS  PubMed  Google Scholar 

  216. 216

    Tschank, G., Raghunath, M., Gunzler, V. & Hanauske-Abel, H. M. Pyridinedicarboxylates, the first mechanism-derived inhibitors for prolyl 4-hydroxylase, selectively suppress cellular hydroxyprolyl biosynthesis. Decrease in interstitial collagen and Clq secretion in cell culture. Biochem. J. 248, 625–633 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217

    Chowdhury, R. et al. Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. ACS Chem. Biol. 8, 1488–1496 (2013).

    CAS  PubMed  Google Scholar 

  218. 218

    Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank N. Heifner for critical help in the development of the manuscript for this article and L. Lasky, B. Hodous and C. T. Walsh for helpful discussions. Some of the initial artwork for this article was provided by F. Forney (www.frankforney.com).

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Correspondence to Robert A. Copeland.

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The authors are all employees and stockholders of Accent Therapeutics.

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Protein Data Bank

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Supplementary information

Supplementary information S1 (figure)

Enzymatic reaction mechanisms of select RNA modifying proteins. (PDF 1208 kb)

Glossary

Chromatin-modifying proteins

(CMPs). A collection of DNA and histone modification writers, erasers and reader proteins that collectively control chromatin modification states and thereby provide the biochemical basis for epigenetic control of DNA transcription.

Epitranscriptomics

Refers to a collection of RNA modification mechanisms that control RNA structure, stability and function, including translation to proteins.

RNA-modifying proteins

(RMPs). A collection of RNA modification writers, erasers and reader proteins that collectively control RNA modification states and thereby provide the biochemical basis for epitranscriptomic control of RNA translation to proteins and other aspects of RNA biology.

NANOG

Gene encoding a DNA homeobox transcription factor involved in embryonic stem cell proliferation, renewal and pluripotency.

Pseudouridine synthase

(PUS). A family of enzymes that catalyse the conversion of uridine to pseudouridine in RNAs.

ADAR

RNA-specific adenosine deaminase. A family of enzymes that catalyse the conversion of adenosine to inosine in RNA.

S-adenosyl-L-methionine

(SAM). The universal methyl-donor substrate of methyltransferase catalysis.

SN2

Bimolecular nucleophilic substitution. A concerted reaction mechanism in which bond cleavage on one reactant occurs simultaneously with bond formation between that reactant and a second reacting molecule.

Transfer RNA methyltransferase

(TRM). A family of enzymes that catalyse the methylation of nucleosides in tRNA.

α-Ketoglutarate

(α-KG). A critical substrate for all enzymes of the Fe2+—α-KG-dependent dioxygenase superfamily.

TET

Ten-eleven translocation protein family. Enzymes within this family catalyse the demethylation of methylcytosine within CpG islands of chromosomal DNA.

RNA demethylases

A collection of enzymes of the ALKB family of dioxygenases that catalyse the demethylation of methylated nucleosides in various forms of RNA.

ALKB

α-Ketoglutarate-dependent dioxygenase. A family of enzymes that catalyse demethylation of methyl-nucleosides in RNA.

Fat mass and obesity-associated protein

(FTO). A member of the ALKB family of RNA demethylases.

YTH

Protein domain family, the members of which function as N6-methyladenosine reader proteins.

m6A-seq

N6-methyladenosine immunoprecipitation sequencing. A method of analysing the m6A content of RNA.

MeRIP-seq

Methylated RNA immunoprecipitation sequencing. A method of analysing the m6A content of RNA.

SCARLET

Site-specific cleavage and radioactive-labelling followed by ligation-assisted extraction and thin-layer chromatography. A method of analysing the m6A content of RNA.

m6A-LAIC-seq

N6-methyladenosine level and isoform-characterization sequencing. A method of analysing the m6A content of RNA.

Methyltransferase-like (METTL) gene family

Encodes enzymes that catalyse nucleoside methylation in RNAs.

RNA methyltransferases

(RNMTs). A family of enzymes that methylate nucleosides within various forms of RNA.

NOL1/NOP2/Sun domain family

(NSUN). A family of enzymes that catalyse methylation of nucleosides in RNAs.

DNA methyltransferases

(DNMTs). A family of enzymes that methylate cytosine within CpG islands of chromosomal DNA.

Protein arginine methyltransferase

(PRMT). A family of enzymes that catalyse methylation of arginine residues in histones and other proteins.

SAH

S-adenosyl-L-homocysteine. The universal product of SAM-dependent methyltransferase catalysis.

Protein lysine methyltransferases

(PKMTs). A family of enzymes that catalyse methylation of lysine residues in histones and other proteins.

Polycomb repressive complex 2

(PRC2). A multiprotein complex that catalyses the methylation of histone 3, lysine 27 (H3K27) using either EZH2 or EZH1 as the catalytic subunit.

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Boriack-Sjodin, P., Ribich, S. & Copeland, R. RNA-modifying proteins as anticancer drug targets. Nat Rev Drug Discov 17, 435–453 (2018). https://doi.org/10.1038/nrd.2018.71

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