Walsh, G. & Jefferis, R. Post-translational modifications in the context of therapeutic proteins. Nat. Biotechnol. 24, 1241–1252 (2006).
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).
Ribich, S., Harvey, D. & Copeland, R. A. Drug discovery and chemical biology of cancer epigenetics. Cell Chem. Biol. 24, 1120–1147 (2017).
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).
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).
Gross, S., Rahal, R., Stransky, N., Lengauer, C. & Hoeflich, K. P. Targeting cancer with kinase inhibitors. J. Clin. Invest. 125, 1780–1789 (2015).
Saletore, Y. et al. The birth of the Epitranscriptome: deciphering the function of RNA modifications. Genome Biol. 13, 175 (2012).
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.
Peer, E., Rechavi, G. & Dominissini, D. Epitranscriptomics: regulation of mRNA metabolism through modifications. Curr. Opin. Chem. Biol. 41, 93–98 (2017).
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.
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).
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).
Singh, H. & Lane, B. G. The alkali-stable dinucleotide sequences in 18s+28s ribonucleates from wheat germ. Can. J. Biochem. 42, 1011–1021 (1964).
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).
Linder, B. et al. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat. Methods 12, 767–772 (2015).
Alarcon, C. R. et al. HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162, 1299–1308 (2015).
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).
Patil, D. P., Pickering, B. F. & Jaffrey, S. R. Reading m6A in the transcriptome: m6A-binding proteins. Trends Cell Biol. 28, 113–127 (2018).
Barnash, K. D., James, L. I. & Frye, S. V. Target class drug discovery. Nat. Chem. Biol. 13, 1053–1056 (2017).
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.
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).
Harcourt, E. M., Kietrys, A. M. & Kool, E. T. Chemical and structural effects of base modifications in messenger RNA. Nature 541, 339–346 (2017).
Edupuganti, R. R. et al. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat. Struct. Mol. Biol. 24, 870–878 (2017).
Karijolich, J., Yi, C. & Yu, Y. T. Transcriptome-wide dynamics of RNA pseudouridylation. Nat. Rev. Mol. Cell Biol. 16, 581–585 (2015).
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).
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).
Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell Biol. 17, 83–96 (2016).
Schubert, H. L., Blumenthal, R. M. & Cheng, X. Many paths to methyltransfer: a chronicle of convergence. Trends Biochem. Sci. 28, 329–335 (2003).
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).
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.
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).
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).
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).
Alemu, E. A., He, C. & Klungland, A. ALKBHs-facilitated RNA modifications and de-modifications. DNA Repair (Amst.) 44, 87–91 (2016).
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.
Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).
Mauer, J. et al. Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 541, 371–375 (2017).
Zhu, Y. et al. LC-MS-MS quantitative analysis reveals the association between FTO and DNA methylation. PLoS ONE 12, e0175849 (2017).
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).
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).
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).
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).
Stoilov, P., Rafalska, I. & Stamm, S. YTH: a new domain in nuclear proteins. Trends Biochem. Sci. 27, 495–497 (2002).
Zhang, Z. et al. The YTH domain is a novel RNA binding domain. J. Biol. Chem. 285, 14701–14710 (2010).
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.
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.
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).
Liu, N. et al. N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560–564 (2015).
Liu, N. et al. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 45, 6051–6063 (2017).
Meyer, K. D. et al. 5′ UTR m6A promotes cap-independent translation. Cell 163, 999–1010 (2015).
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).
Li, X., Xiong, X. & Yi, C. Epitranscriptome sequencing technologies: decoding RNA modifications. Nat. Methods 14, 23–31 (2016).
Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).
Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).
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).
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).
Xiao, W. et al. Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol. Cell 61, 507–519 (2016).
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).
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).
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).
Coots, R. A. et al. m6A facilitates eIF4F-independent mRNA translation. Mol. Cell 68, 504–514.e7 (2017).
Patil, D. P. et al. m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369–373 (2016).
Zhang, C. et al. m6A modulates haematopoietic stem and progenitor cell specification. Nature 549, 273–276 (2017).
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).
Yoon, K. J. et al. Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell 171, 877–889.e17 (2017).
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.
Geula, S. et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science 347, 1002–1006 (2015).
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.
Schwartz, S. et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell 155, 1409–1421 (2013).
Safra, M. et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251–255 (2017).
Li, X. et al. Base-resolution mapping reveals distinct m1A methylome in nuclear- and mitochondrial-encoded transcripts. Mol. Cell 68, 993–1005.e9 (2017).
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).
Squires, J. E. et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 40, 5023–5033 (2012).
Motorin, Y., Lyko, F. & Helm, M. 5-Methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res. 38, 1415–1430 (2010).
Li, X. et al. Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat. Chem. Biol. 11, 592–597 (2015).
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).
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.
Su, R. et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 172, 90–105.e23 (2018).
Barbieri, I. et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature 552, 126–131 (2017).
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).
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).
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).
Cui, Q. et al. m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 18, 2622–2634 (2017).
Visvanathan, A. et al. Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37, 522–533 (2018).
Hsu, P. J., Shi, H. & He, C. Epitranscriptomic influences on development and disease. Genome Biol. 18, 197 (2017).
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).
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).
Goodarzi, H. et al. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell 165, 1416–1427 (2016).
Yu, Y. P. et al. Novel fusion transcripts associate with progressive prostate cancer. Am. J. Pathol. 184, 2840–2849 (2014).
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).
Frye, M. et al. Genomic gain of 5p15 leads to over-expression of Misu (NSUN2) in breast cancer. Cancer Lett. 289, 71–80 (2010).
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).
Yi, J. et al. Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer. Oncotarget 8, 20751–20765 (2017).
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).
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).
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).
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).
Dina, C. et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat. Genet. 39, 724–726 (2007).
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).
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).
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).
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).
Fahiminiya, S. et al. Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar. Clin. Genet. 86, 134–141 (2014).
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).
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).
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).
Lichinchi, G. et al. Dynamics of human and viral RNA methylation during Zika virus infection. Cell Host Microbe 20, 666–673 (2016).
Gokhale, N. S. et al. N6-methyladenosine in flaviviridae viral RNA genomes regulates infection. Cell Host Microbe 20, 654–665 (2016).
Kennedy, E. M. et al. Posttranscriptional m6A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe 19, 675–685 (2016).
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).
Jonkhout, N. et al. The RNA modification landscape in human disease. RNA 23, 1754–1769 (2017).
Torres, A. G., Batlle, E. & Ribas de Pouplana, L. Role of tRNA modifications in human diseases. Trends Mol. Med. 20, 306–314 (2014).
Leelananda, S. P. & Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem. 12, 2694–2718 (2016).
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).
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).
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).
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).
Byszewska, M., Smietanski, M., Purta, E. & Bujnicki, J. M. RNA methyltransferases involved in 5′ cap biosynthesis. RNA Biol. 11, 1597–1607 (2014).
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).
Richon, V. M. et al. Chemogenetic analysis of human protein methyltransferases. Chem. Biol. Drug Des. 78, 199–210 (2011).
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).
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).
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).
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).
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.
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).
Smietanski, M. et al. Structural analysis of human 2′-O-ribose methyltransferases involved in mRNA cap structure formation. Nat. Commun. 5, 3004 (2014).
Wang, X. et al. Structural basis of N6-adenosine methylation by the METTL3-METTL14 complex. Nature 534, 575–578 (2016).
Wang, P., Doxtader, K. A. & Nam, Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol. Cell 63, 306–317 (2016).
Sledz, P. & Jinek, M. Structural insights into the molecular mechanism of the m6A writer complex. eLife 5, e18434 (2016).
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).
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).
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).
Boriack-Sjodin, P. A. & Swinger, K. K. Protein methyltransferases: a distinct, diverse, and dynamic family of enzymes. Biochemistry 55, 1557–1569 (2016).
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).
Gerken, T. et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472 (2007).
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).
Yu, B. et al. Crystal structures of catalytic complexes of the oxidative DNA/RNA repair enzyme AlkB. Nature 439, 879–884 (2006).
Sundheim, O. et al. Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damage. EMBO J. 25, 3389–3397 (2006).
Yang, C. G. et al. Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNA. Nature 452, 961–965 (2008).
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).
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).
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).
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).
Feng, C. et al. Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition. J. Biol. Chem. 289, 11571–11583 (2014).
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).
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).
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).
Han, Z. et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464, 1205–1209 (2010).
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).
Aik, W. et al. Structural basis for inhibition of the fat mass and obesity associated protein (FTO). J. Med. Chem. 56, 3680–3688 (2013).
Huang, Y. et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 43, 373–384 (2015).
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).
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).
Chen, Y. & Varani, G. Protein families and RNA recognition. FEBS J. 272, 2088–2097 (2005).
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).
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).
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).
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).
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).
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).
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).
Gu, M. et al. Insights into the structure, mechanism, and regulation of scavenger mRNA decapping activity. Mol. Cell 14, 67–80 (2004).
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).
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).
Wu, M. et al. Structural basis of m7GpppG binding to poly(A)-specific ribonuclease. Structure 17, 276–286 (2009).
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).
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).
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).
Gnyszka, A., Jastrzebski, Z. & Flis, S. DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer. Anticancer Res. 33, 2989–2996 (2013).
Kaniskan, H. U., Martini, M. L. & Jin, J. Inhibitors of protein methyltransferases and demethylases. Chem. Rev. 118, 989–1068 (2018).
Jambhekar, A., Anastas, J. N. & Shi, Y. Histone lysine demethylase inhibitors. Cold Spring Harb. Perspect. Med. 7, a026484 (2017).
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).
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).
James, L. I. et al. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat. Chem. Biol. 9, 184–191 (2013).
Barnash, K. D. et al. Discovery of peptidomimetic ligands of EED as allosteric inhibitors of PRC2. ACS Comb. Sci. 19, 161–172 (2017).
Qi, W. et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat. Chem. Biol. 13, 381–388 (2017).
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).
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).
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).
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).
He, Y. et al. The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol. 13, 389–395 (2017).
Sanchez, R., Meslamani, J. & Zhou, M. M. The bromodomain: from epigenome reader to druggable target. Biochim. Biophys. Acta 1839, 676–685 (2014).
Galdeano, C. Drugging the undruggable: targeting challenging E3 ligases for personalized medicine. Future Med. Chem. 9, 347–350 (2017).
Arrowsmith, C. H. et al. The promise and peril of chemical probes. Nat. Chem. Biol. 11, 536–541 (2015).
Copeland, R. A. & Boriack-Sjodin, P. A. The elements of translational chemical biology. Cell Chem. Biol. 25, 128–134 (2018).
Copeland, R. A. Evaluation of Enzyme Inhibitors in Drug Disovery: A Guide for Medicinal Chemists and Pharmacologists 2nd edn (Wiley, 2013).
Boccaletto, P. et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 46, D303–D307 (2018).
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).
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).
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).
Okamoto, M. et al. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells. PLoS Genet. 10, e1004639 (2014).
Zhang, Z. et al. METTL13 is downregulated in bladder carcinoma and suppresses cell proliferation, migration and invasion. Sci. Rep. 6, 19261 (2016).
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).
Job, B. et al. Genomic aberrations in lung adenocarcinoma in never smokers. PLoS ONE 5, e15145 (2010).
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).
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).
Couch, F. J. et al. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nat. Commun. 7, 11375 (2016).
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).
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).
Yao, L. et al. Elevated expression of RNA methyltransferase BCDIN3D predicts poor prognosis in breast cancer. Oncotarget 7, 53895–53902 (2016).
Shimada, K. et al. A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. Cancer Res. 69, 3157–3164 (2009).
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).
Hoff, A. M. et al. Identification of novel fusion genes in testicular germ cell tumors. Cancer Res. 76, 108–116 (2016).
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).
Su, H. et al. Elevated snoRNA biogenesis is essential in breast cancer. Oncogene 33, 1348–1358 (2014).
Ikeda, S. et al. Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma. Cancer Sci. 108, 641–652 (2017).
Ueda, Y. et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells. Sci. Rep. 7, 42271 (2017).
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).
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).
Chen, J. et al. YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle 16, 2259–2271 (2017).
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).
Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).
Chowdhury, R. et al. Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. Structure 17, 981–989 (2009).
Rose, N. R. et al. Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. J. Med. Chem. 51, 7053–7056 (2008).
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).
Chowdhury, R. et al. Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. ACS Chem. Biol. 8, 1488–1496 (2013).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).