Posted on Authorea 9 Nov 2020 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.160495480.00891340/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. ABSTRACT title: Running [email protected] e-mail M.E. or M.B. to *Correspondence 6 Spain. Catalonia, celona, 5 Spain. Catalonia, Barcelona, Badalona, 4 (IJC), Institute Research Leukaemia reras 3 Spain. Catalonia, Barcelona, Spain. Catalonia, 2 Barcelona, Badalona, Institute, Research kaemia 1 cancer in modifications RNA target Mar´ıa Berdasco that Compounds Treatment epitranscriptome: and “druggable” Prevention a Cancer Towards in Avenues New on section Themed benefit. clinical for targeted-RNA of an challenges ARTICLE potential provide principal the REVIEW and the increase cancer discuss to development will in mod- we drug dysregulation Finally, and RNA their biology principal epitranscriptome. of chemical the the evidences of describe target scientific field will to the latest we discovery in the drug review, aberrant state-of-the-art this summarize of the In discovery mRNA), offers of the intervention. on epitrancriptomics overview by molecule whether focus small- see fueled a to by been (with now targeted has post-transcripcional is ifications be of interest challenge to map scientific The mechanims a the cancer. tunable to However, mainly led a diseases, have develoment. human which and with tech- modifications fate the associated RNA by cell epitranscriptomes quantify boosted normal and is characterize in field to The marks decade RNA. RNA of last modifications the biochemical of studies efforts that nical area emerging exciting an is Epitranscriptomics Abstract 2020 9, November 1 Berdasco Maria cancer target in that modifications Compounds RNA epitranscriptome: “druggable” a Towards nttc´ aaaad eec sui vnct IRA,Breoa aaoi,Spain. Catalonia, Barcelona, Avan¸cats (ICREA), Estudis Bar- i Recerca Barcelona, de of Instituci´o Catalana University Sciences, Health and Medicine of School Department, Sciences Physiological Spain. Madrid, Car- C´ancer (CIBERONC), Investigaci´onRed Josep Biom´edica de en (PEBCL), Program Centro Biology and Epigenetics Leukemia (IDIBELL), and Cancer Institute Group, Research Epigenetics Biomedical Cancer Bellvitge (PEBC), Program Biology and Epigenetics Cancer Leu- Carreras Josep (PHEC), Program Hematology Clinical and Experimental Group, Therapies Epigenetic oe arrsLuamaRsac nttt (IJC) Institute Research Leukaemia Carreras Josep [email protected]; rg httre N oicto nye ncancer. in enzymes modification RNA target that Drugs 1,2,* 1 n ae Esteller Manel and n ae Esteller Manel and 1 3,4,5,6* 1 Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ioeottfrteteteto L-uinluama(ti ta. 08.Opruiishv extended have Opportunities 2018). inhibitor al., DOT1L et the (Stein or leukaemia 2018) treat the MLL-fusion al., to line, of trial et this treatment clinical (Italiano In the amplification II/III 2020). for EZH2 Phase mu- al., pinometostat with a genetic (Coss´ıo et reached lymphoma of therapy tazemotostat non-Hodgkin presence targeted inhibitor refractory Panobinostat) the more EZH2 CML explore a (HMT) development refractory methyltransferase as epidrug in histone enzymes in routine epigenome-modifying approaches clinical of New deacetylase for tations of histone 2018). approval Similarly, treatment Popat, FDA- 2016). the and reached al., (Cavenagh et (AML), for also Diesch leukaemia have 2014; practice myeloid al., inhibitors clinical et acute (HDAC) (Prebet into (MDS), (CML) leukaemia implemented syndromes myeloid myelodysplastic chronic been and as have epigenetic such decitabine target malignancies, as that haematological such inhibitors (“ inhibitors small-molecule histones (DNMT) (“ of and modifications range DNA these (“ into The interpret tags groups activity chemical chemical 2019). de- epigenetic add these al., and with move that discovery et enzymes enzymes (Berdasco the Jones of improved include modifiers) pocket 2019; has proteins epigenetic catalytic disease al., the in affecting et targeting alterations mutations (Ganesan epigenetic compounds genetic of germline-related small-molecule deviations. knowledge with of also to Our velopment associated but subject 2018). pathologies) disorders also Esteller, cardiovascular rare is and or setting including diseases orchestrated (e.g. disorders, infectious This human diseases differenti- disorders, multiple cell 2020). and neurological with al., development and associated cancer, et normal replication are Dai guide cell alterations to during 2016; signals Epigenetic Jenuwein, stable environmental is and specific that (Allis control by post- landscape the ation and modulated epigenetic in methylation/demethylation be an role DNA could set accepted that processes. histones an biological of has DNA-related modifications mechanisms other translational epigenetic and by expression mediated gene structure of chromatin of control The regions. lymphoma; untranslated T-cell UTR, peripheral RNA; INTRODUCTION. transfer PTCL, 1. tRNA, xenograft; S-adenosylmethionine; patient-derived SAM, PDX, RNA; RNA; non-coding cancer; ribosomal ncRNA, N6- lung rRNA, microRNA m6A, cell miRNA, RNA; non-small cytidine; messenger acid NSCLC, mRNA, 5-methyl meclofenamic myeloma; of multiple m5C, form MM, ester ethyl N1-methyladenosine; syndrome; MA2, Carcinoma m1A, acid; 5- meclofenamic Squamous hm5C, MA, methyltransferases; Neck methyladenosine; desacetylases; and protein Head histone lysine HNSCC, HDAC, methyltransferases; KMT, carcinoma; histone DNA HMT, hepatocellular transition; DNMT, cytidine; HCC, epithelial-mesenchymal hydroxylmethyl lymphoma; EMT, multiforme; T-cell carcinoma; glioblastoma cutaneous cell CTCL, GBM, squamous leukaemia; oesophageal myeloid ESCC, chronic methyltransferases; CML, regions; coding CDS, Ψ, ABBREVIATIONS can- therapy, inhibitors, cer. small-molecule A-to-I-editing, pseudouridine, methylation; RNA Epitranscriptomics, and will cancer we potential the in Finally, increase epitranscriptome. dysregulation to KEYWORDS development the drug their benefit. and target clinical of biology chemical to for be evidences of modifications discovery targeted-RNA field to scientific RNA of the drug mechanims in latest principal state-of-the-art challenges tunable principal the the the the a describe discuss of summarize diseases, will offers overview mRNA), human we epitrancriptomics an on with review, provide whether this focus associated see In a epitranscriptomes intervention. scientific to (with aberrant the molecule now However, small- of develoment. is by and discovery challenge fate targeted the The cell by normal cancer. have in fueled which mainly marks modifications is been RNA RNA field quantify has post-transcripcional and The characterize of interest RNA. to map of decade a last modifications to the biochemical of led studies efforts technical that the area by emerging boosted exciting an is Epitranscriptomics suordn;At-,Aeoiet-nsn;AL ct yli ekei;AA 5-azacytidine; AZA, Leukaemia; Myeloid Acute AML, Adenosine-to-Inosine; A-to-I, pseudouridine; erasers” erasers” n pcfi idn oanpoen htaeal oietf and identify to able are that proteins domain binding specific and ) Gnsn 08 aea ta. 09.DAmethyltransferase DNA 2019). al., et Ganesan 2018; (Ganesan, ) 2 writers enovo de ; D,myelodysplastic MDS, ) rtista re- that proteins ”), pmttos(e.g., epimutations Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. 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In complete on not are expression. a does they gene obtaining of RNA which from epitranscrip- regulation that in far of pathways is still field however, biological are the we of dences, and efforts, progression and all molecular and infancy Despite the onset its and examined. the in recently on still impact been is their has dynamism tomics addition, cancer, RNA range In biogenesis, especially ( that RNA conditions. characterized diseases, for pseudo-uridine sites physiological human and important under 5hmC), modification be identified function to as harbour have RNA known and we are can known that Nowadays, sugar also modifications (m5C; (m1A). ribose posttranslational (hm5C; cytidine N1-methyladenosine mRNA the 5-methyl cytidine and (I), as 5-hydroxylmethyl (m6A) inosine well 5mC), including methyladenosine as as modifications, U) chemical known construct to C, to also processes T, started isomerization we (A, base have bases from decade RNA past four the during The only RNAs: is of (Boccaletto abundant it maps identified However, most first been 2017a). the the have al., affecting molecules last et them RNA the (Roundtree of Over in (tRNA) most epitranscriptomes. modifications these 2018), aberrant posttranslational of al., with 140 targeting et diseases than pharmacological human more the in years RNA for strategy the 50 intervention at possibilities an modifications new as post-translational opened of modifications have role “epitranscriptome”) the on (termed discoveries companies level recent of biotech model, volume and epigenetic The the industry Following 2020). pharmaceutical al., market. of et epigenetic-based sector Villanueva meta- the R&D 2019; and boosted Esteller, academia, cardiovascular have is and in diseases, defects Berdasco conducted brain epigenetic 2017; research revert to Li, epigenetic to diseases and able infectious (Ballestar agents from disorders therapeutic ranging bolic as pathologies, drugs other epigenetic to of extending potential the and cancer beyond messenge N mN)mdfiain n oevso hi mato eeregulation. gene on impact their envision to and modifications (mRNA) RNA r versus H EPIGENOME. 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Data may be preliminary. elrpormigi lrptny(hne l,21) hsfidn enocstecosakbtenthe between crosstalk the influences reinforces and regulation. finding mechanism gene This of pairing 2015). control sequence the al., in a et 2018). epitranscriptome miRNA (Chen via al., and specific pluripotency epigenome modification et into in incorporated Huang m6A reprogramming be 2017; regulate And could cell al., 2015b). microRNAs m6A et al., that that (Alarc´on et (Shi suggest miRNA-binding described UTRs decay modulate 3’ to RNA in YTHDC1 sequences and IGF2BP1/2/3, m6A target 2016). YTHDF3, of process al., YTHDF1, deposition translation to et including the addition RNA Strikingly, In proteins, Xiao 2017b). the reader 2015; al., m6A supervise et al., (Roundtree splicing, YTHDC2, et cytoplasm and into Liu hnRNPA2B1 stability RNAs mammalian and RNA 2015a; processed 2020), of hnRNPG, regulating al., export hnRNPC, al., (Alarc´on nuclear et YTHDC1, metabolism mediate et splicing lipid pre-mRNA, also 2017a; (Heck mRNA could in on involved al., modulate cells m6A genes recognizing also et downstream stem By of could (Zhang pluripotency 2018). regulation al., induced circadian specification or et from cell 2017) (Zhong induction al., postranscriptional progenitor et neural of and (Hsu 2018b), spermatogenesis aspects stem the al., of instance, haematopoietic et For almost as translation. Li in such and involved splicing processes stability, controls is YTHDF2 mRNA modulates m6A and including why YTHDF1 cycle, readers explain life future. m6A mRNA near could of of and the readers integration regulation in layer of the gene expected new on range is a focused control wide scenario gene adds The research explain methylation anticipated to 2019a). RNA An signals al., expression. m6A epitranscriptomic et gene and and (Huang of epigenetic H3K36me3 sites control H3K36me3 the histone of with in de- between trimethylation recruiting overlapped complexity studies by that association peaks (ChIP)-sequencing sequences m6A the described immunoprecipitation genomic of codon Altogether, been Chromatin specific 70% stop 2019a). has approximately into the that al., it deposition of monstrated et Interestingly, m6A upstream (Huang influences 2012). just complex (H3K36me3) al., enrichment METTL14 Lys36 et significant regions at Meyer coding a H3 the 2012; with histone in al., mainly (UTR) manner, et regions dependent untranslated (Dominissini sequence- a 3’ in and occurs (CDS) mRNA (hnRNP) on al., ribonucleoproteins deposition et nuclear m6A Generally, (Xiao heterogeneous proteins) some YTHDC and proteins 2018), and identified, 2015a). ALKBH5 al., (YTHDF also al., et family and (Alarc´on been al., et (Huang YTH have FTO et proteins the readers (Jia IGF2BP demethylases. m6A to (FTO) 2016), 2013) belonging acids. protein al., proteins nucleic obesity-associated N-methylated m6A-binding et and modifi- demethylate included (Zheng mass this to (ALKBH5) fat transcriptome, known splicing 5 dioxygenases the the mRNA cellular are homologue of of the demethylation activity the AlkB in m6A the and of as passive by 2011) regulation well removed from as the actively Apart methylation, is in the 2017). for cation involved as al., donor is et acts methyl (Pendleton METTL16 METTL14 the process (SAM), and methyltransferase. 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RNA scenarios AND research CODING major NON-CANONICAL the discovery. introduce 3. drug will knowledge in we of target level sections, current actionable effect next the an and In the complex modifications tremendously though limited. is indirectly somewhat word” “RNA still also the is that but assume targets can we since their together, functionally, by All works directly modification read the change. how be structural influence their could also on modifications change RNA conformational in This changes 2015). al., et (Liu iue1 Figure 6mtyaeoie(6)i h otaudn nenlmdfiainde- modification internal abundant most the is (m6A) N6-methyladenosine .Temtytaseaelk MTL)MTL4htrdmris heterodimer (METTL3)–METTL14 3 methyltransferase-like The ). \ oth RAsaiiydrn tmcl ieetainand differentiation cell stem during stability mRNA soutthe ldzadJnk 06.AohrmAwie rti is protein writer m6A Another 2016). Jinek, Sled´z and ´ 4 ldzadJnk 06.Isaudnetogether abundance Its 2016). 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Data may be preliminary. o DR ntecnrlo h icda lc a enrvae Trjm ta. 2017). role al., et A (Terajima 2017). revealed CANCER. been al., for IN has et required clock EPITRANSCRIPTOME (Behm primarily DEREGULATED circadian development is the 4. system and of long brain nervous control of in central the expression editing for in higher promote promiscuous ADAR2 transcripts to a in for Dicer key has with role ADAR2 of complex prominent a editing 2013). forms a al., ADAR1 site-specific plays that et especially indicate (Ota and studies expressed, processing ADAR2 system, Additional widely miRNA and 2016). blood is ADAR1 al., ADAR1 the et Both mammals, may of (Zipeto 2016b). dsRNA In and component (Nishikura, myeloid differentiation. activity activity cellular the editing ADAR2 in lacks in and roles ADAR3 ADAR1 essential whereas of have proteins, regulator proteins negative active a catalytically same as the the act are within ADAR2 2017). other regions by and al., with each ADAR1 catalysed et associated to mostly (Porath is proximity is UTRs edition editing close 3’ A-to-I of and in class regions this adenosines intronic mammals, of sequences, In as repetitive proportion hyper-editing. against understood of for large protecting requisite be A in a sec- could role is A which 2014). transcript A 2018). hyper-editing, al., Levanon, process. is and et editing editing (Eisenberg (Porath that the A-to-I proposed revealed for of been have targets modifications type self-transcripts pro- main ond A-to-I by as the immunity animal well were innate as among of genome mRNAs and, study activation the or guanine comparative miRNAs of a a of parts like However, function non-coding level and/or cellular 2016b). biogenesis at the (Nishikura, repeats, interpreted alter Alu teins could is ( (e.g., editing regions Inosine editing I non-coding A-to-I 2016a). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. eerhamda eeoigslcieadcl-ciesalmlcl niioso lBsbaiisof subfamilies AlkB of inhibitors molecule small cell-active and the 2015). selective modulate al., and developing et (Wang demethylation at cells FTO living aimed inhibit of with FTO Research derivatives efficiently mRNA inhibited fluorescein the could Two selectively in FL8, derivatives) with 2015). m6A molecules al., its and of fluorescent et of level of FL6 (Wang many design protein permeability, some of FTO the screening (and cell labelled facilitated a improved fluorescein directly has on as that based ALKBH5 well revealed over study as MA demethylation a FTO step, to for later selectivity similar 2018). a MA structures al., In for et improving inhibitors. 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Data may be preliminary. hr r nqeRAmdfiain htcudntb oprdwt N rhsoemdfiain.The modifications. histone or DNA with al., compared et be (Soukarieh not doses could that physiological modifications at RNA activity unique inhibitory are role with transformation, There its in cell compounds Through evaluated in of were implicated 2016). set eIF4E is al., a 2016). of eIF4E initiation et provides inhibitors pathways, translation (Soukarieh and Guanine-based oncogenic eukaryotic proposed assays of reader been angiogenesis. translation m7G have and mRNA the target tumorigenesis, of inhibit actionable regulation be an to contribute the to and needs as Efforts in effect still (eIF4E) It tissue-specific 2019). 4E a homology. 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. em . altd,H,Wdak . rksn . and M., Eriksson, A., Widmark, H., ChemMedChem Wahlstedt, Writer. L., M., Epitranscriptomic Behm, Wiedmer, Human Major S.A., the Eberle, METTL3, of D., Inhibitors Huang, Promoter- Nature R.K., (2017). control. al. translation Bedi, et m6A-dependent S.C., by leukaemia Robson, Mill´an-Zambrano, myeloid Cancer G., J., maintains Rev. Shi, METTL3 Nat. L., bound cancer. Pandolfini, in K., modifications Tzelepis, RNA I., Nat. of Barbieri, diseases. Role (2020). rheumatic T. inflammatory Kouzarides, of and epigenetics I., Barbieri, the into insights lung New (2017). human Rheumatol. T. Rev. enhances Li, ADAR1 and E., enzyme Ballestar, (2016b). editing al. RNA Mart´ınez-Card´us, et the F., Oncogene A., of Setien, tumourigenesis. overexpression lung C., amplification-associated human Moutinho, Sim´o-Riudalbas,Gene L., enhances S., ADAR1 Guil, enzyme Anad´on, C., (2016a). editing al. RNA Mart´ınez-Card´us, et the F., A., Oncogene of Setien, tumourigenesis. overexpression C., Genet. amplification-associated Moutinho, Rev. Sim´o-Riudalbas,Gene L., Nat. S., control. epigenetic Guil, of Anad´on, C., hallmarks molecular The (2016). T. 487–500. marks Jenuwein, N6-methyladenosine and (2015b). C.D., S.F. Allis, Tavazoie, Nature and processing. N., a for Halberg, Is microRNAs H., HNRNPA2B1 primary (2015a). Goodarzi, S.F. H., Cell Tavazoie, Lee, Events. and Alarc´on, C.R., Processing S., RNA Tavazoie, Nuclear X., m6A-Dependent Liu, of H., Mediator Lee, H., Goodarzi, innovativeAlarc´on, C.R., of reality. and development exciting health the an human be Science”, in References will role “epitranscriptome modifications its of RNA clearer and and of pathways overview intervention better signalling comprehensive a therapeutic to have this contribution will its With we et map, barriers, disease. (Morena technical epitranscriptome data and the biological the of chemical, of view other) reliability (and generate, the these ensure to overcoming to In tools priority bioinformatic a modifi- of also development RNA be specific 2018). or should in low-abundance al., controls protocols epitranscriptome of as standardize the quantification and of standards and analyse, precision internal and site-specific identification of quantification (Zhang establishment or the better m6A-REF-seq cations, recognition for a or allow advances antibody 2019) to Technological al., on promises contexts. et NGS dependent held (Garcia-Campos using 2019), methods MAZTER-seq scale al., avoid wide like et at radiolabelling, to draws par- epitranscriptome to Improvements improvement, also the linked 2015). undoubtedly, tremendous studying cleavage a knowledge, for al., shown methods This et have valid effect. of (Linder methods pleiotropic development detection the a drugs modification since prevent associated RNA ticularly of intense to side. toxicity of difficult technical the aspect increase the extremely An could from be 2014). modifications mo- al., would RNA small et of it Wang of nature as complexity 2011; consequences ubiquitous al., the biological the whether et the and is evaluate (Jia modifications debate to epitranscriptome RNA the impediment possible targeting an intervention of still lecules number are involved high pathways the molecular improvements, epigenetic other of seeing on histone are effects and we unforeseen DNA Although induce with can cofactors of epigenetics. modifications most and including RNA 2019a), sites systems on of al., intervention regulation catalytic function et drug-based physiological shared Huang thus, the 2018; enzymes and unravel al., machinery, modifying to et RNA direction (Cheng right actual described the previously the in as move Furthermore, a modifications. are RNA enzymes) RNA-modifying for mice 13 593–605. : 35 35 4407–4413. : 4407–4413. : 519 482–485. : 15 ldz . n aic,A 22) Small-Molecule (2020). A. Caflisch, and P., Sled´z, ´ ha,M 21) cuuaino nuclear of Accumulation (2017). M. Ohman, ¨ 162 1299–1308. : 15 744–748. : 552 20 126–131. : 303–322. : 17 : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. hn . i . u,B-. ag . a,Y-. un . ta.(09.5mtyctsn promotes 5-methylcytosine (2019). al. et X., Biol. Yuan, Cell Is Y.-N., Nat. Methylation Han, mRNAs. RNA Y., stabilizing m6A Yang, through (2015). cancer B.-F., bladder Sun, al. Cell of et A., Stem pathogenesis W., Cell Li, Han, editing Pluripotency. X., M., to RNA Chen, Wang, Reprogramming Recoding M.-M., Promotes 6 (2013). Li, and N Y., MicroRNAs al. Cell-Active by Zhang, et of Regulated Y.-J., Y., Development Med. Hao, Song, T., Nat. R.K.K., (2012). Chen, Chow, carcinoma. T.H.M., hepatocellular al. to Chan, et predisposes C.H., X., AZIN1 Lin, of Zhang, Soc. Y., X., Li, Chem. L., Huang, Am. Chen, J. G., in Inhibitor. Jia, Roles FTO L., Potential Demethylase RNA Yu, RNA Its ADAR-Mediated F., -Methyladenosine and Ye, NSUN2 (2016). B., Methyltransferase Chen, RNA al. The et L., (2020). Cells S.G. Qi, Cancer. Gray, H., Gastroenterology and Yang, Cancer. A., Gastric J., Chellamuthu, of Guo, Prognosis K.T., and Progression balance Tan, editing Predicts A., RNA Editing Gut disrupted Qamra, A carcinoma. T.H.M., hepatocellular (2014). Chan, human al. in et RNA) K.J., on class Yong, act 832–843. Y., common that Li, : DeAminases A -methyladenosine J., (Adenosine Fei, 1 ADARs (2017). L., by N Qi, mediated and al. C.H., features, Lin, et T.H.M., sequence A.F., Chan, coding Palazzo, M.P., early Snyder, distinct RNA A., depletion, Akef, 5’-intron modification. G., with Singh, transcripts Inhibitor-Related H.N., of Myeloma Deacetylase Chua, Lymphoma. Histone C., Clin. of Cenik, Panobinostat. Management on Focus Optimal A Myeloma: (2014b). Multiple (2018). Leuk. V. With Patients R. W. in Events Popat, Gilbert, Adverse Nature and and cells. J.D., K.M., human Cavenagh, and Bartoli, yeast H., in Shin, pseudouridylation (2014a). mRNA B., 143–146. V. regulated Zinshteyn, reveals W. profiling M.F., Gilbert, Pseudouridine Nature Rojas-Duran, and cells. T.M., K.M., human Carlile, and Bartoli, yeast H., in Shin, pseudouridylation mRNA B., 143–146. regulated Zinshteyn, reveals drug profiling M.F., anticancer Pseudouridine as Rojas-Duran, proteins T.M., RNA-modifying Carlile, Discov. (2018). Drug R.A. Rev. Copeland, Nat. and targets. S., Ribich, (2019). A112–A112. P.A., Drug pp al. In Boriack-Sjodin, Research), et METTL3/METTL14. Cancer E.A., methyltransferase for protein Sickmier, RNA Association M., the (American Laidlaw, on Design, S.M., efforts discovery (2018). Res. Buker, Drug T.A., Acids A112: Wynn, al. Nucleic Abstract A.K., et Gardino, update. P.A., T.K., 2017 Boriack-Sjodin, Wirecki, pathways. B., Bagi´nski, modification P., RNA Piatkowski, of D307. E., database Rev. Purta, a Nat. M.A., MODOMICS: translation. Machnicka, for P., opportunities Boccaletto, seizing epigenetics: Clinical (2019). Rev. M. Nat. Genet. Esteller, translation. and for M., opportunities Berdasco, seizing epigenetics: Clinical (2018). M. Genet. Esteller, Sci. and Cell M., J. Berdasco, development. neuronal during editing 753. RNA adenosine-to-inosine regulates ADAR2 18 20 501–507. : 109–127. : 9 1758. : 23 270–283. : 17 435–453. : 16 19 209–216. : 134 21 17963–17971. : 978–990. : 151 637-650.e10. : 16 289–301. : 46 130 D303– : 745– : 515 515 63 : : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. u . oiisn,D,Rcai . n e .(04.Gn xrsinrglto eitdthrough mediated regulation expression Gene (2014). C. He, Genet. Rev. and Nat. G., methylation. Rechavi, RNA m6A D., reversible Proli- Dominissini, Myc-Induced Mediates Biol. Y., (NSun2) Curr. Fu, Tumours. Misu in Methyltransferase Upregulated RNA Is The and Conferring (2006). feration F.M. Collagen Watt, Targets and Lymphoma M., Hodgkin Frye, 10.1182/blood.2020005823. in doi: ALKBH3 Blood (2020). Demethylase Outcome. al. Clinical RNA et Poor m1A M., Encuentra, of V., Davalos, Loss E., Epigenetic Domingo-Domenech, Pi˜neyro, D., F., Discov. Climent, Cancer R., Cancer. Esteve-Puig, in Com- RNAs Mutation, Noncoding of IDH Epitranscriptome (2017). The al. 7 (2017). P.P. et Cell Pandolfi, P.L.M., and Cancer Dahia, M., Methylation. Esteller, D., RNA Jiang, and di- H., FTO, transcriptome Sill, of J., and Inhibition Myers, petitive protector A.-P., immune Lin, — S.M., editing Elkashef, RNA promotes A-to-I Genet. ADAR1 (2018). Rev. of Nat. E.Y. overexpression versifier. Levanon, Aberrant (2016). and Y. Oncotarget E., Gao, signaling. Eisenberg, and mTOR/p70S6K Y., activating Li, by D., progression Yang, cancer X., gastric Ye, (2016). S., Nature Yu, al. RNA. et N., Nature messenger M.S., Dou, eukaryotic Ben-Haim, m6A-seq. in N., methylome by Kol, E., N1-methyladenosine revealed Peer, dynamic S., methylomes The Moshitch-Moshkovitz, S., RNA Nachtergaele, al. m6A D., et Dominissini, mouse S., Osenberg, and L., human Ungar, the M., 201–206. of Salmon-Divon, Epigenetics S., Topology Clin. Schwartz, (2012). cancers. S., G hematologic Moshitch-Moshkovitz, of and D., treatment M., Dominissini, the Buschbeck, for A., therapy METTL3 Palau, azanucleoside-based methyltransferase A.-K., on m6A Garz, update A., (2019). Zwick, al. Ther. Targets. J., et Onco. Diesch, P., pathways. Li, p38/ERK R., through Huang, migration 12 J., and Volume proliferation Zhang, cancer S., colorectal Ye, and suppresses Y., biology chromatin Cheng, of R., landscape Deng, metabolic evolving The Genet. (2020). Rev. J.W. Nat. Proteins Locasale, Domain-Containing epigenetics. and Chem. V., YTH Anal. Ramesh, of RNA. Z., Identification in Dai, (2018). 1-Methyladenosine Y. N Wang, for of and Readers invasiveness G., the the regulates Gonzalez, as Regulates METTL3 T., Wang, methyltransferase Methylation Res. X., m6A Melanoma RNA Dai, RNA 2. A (2019). metallopeptidase 6 M. matrix by Gupta, m cells and (2017). Discov. melanoma Drug K., al. Rev. Le, Nat. et U., mark. epigenetic G., Dahal, RNA their Sun, make inhibitors Q., Rep. Chemical Qu, Cell (2019). M. Cells. L., Cully, Stem Li, Glioblastoma Exploring P., of Tumourigenesis Ye, cancer: and in H., Self-Renewal therapy Shi, and precise Q., methylation more Cui, cytosine a Biol. Towards RNA Chem. (2020). Opin. (2018). M. Curr. complexity. Berdasco, epigenetic al. and et M., J., leukaemia. Esteller, Coss´ıo, Wei, in F.P., resistance M., and Yue, Oncol. response A., Commun. 5-azacytidine J. Cloe, and Nat. organization Y., functions Int. chromatin ADAR2 Li, mediate carcinoma. L., (2017). methyltransferases cell Chen, al. squamous J.X., et esophageal Cheng, L., in Zhang, IGFBP7 H.-D., editing Qin, via F., suppressor 622–630. Wang, tumour J.-B., a Zhang, as X.-Y., Liao, Y.-B., Chen, 359–368. : 4391–4402. : 9 1163. : 19 473–490. : 57 41–49. : 17 15 16 293–306. : 971–981. : 29 90 31 382–389. : 6380–6384. : 619–620. : te ..(06.Aclinical-molecular A (2016). K.S. ¨ otze, 18 2622–2634. : 7 86161–86173. : 530 441–446. : 18 892–894. : 8 71. : 485 50 : : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. siua .. ags,RT,Ceuyt .. i . ad,A,Iaht-ele . ta.(09.Ls of Loss (2019). Nature al. shows blockade. et FTO checkpoint A., immune Iracheta-Vellve, in variant to A., Panda, resistance A overcomes K., (2013). Bi, tumours al. C.K., in et Cheruiyot, Genet. ADAR1 R., R.T., Nat. Manguso, BMI. Pfeiffer, J.J., to S., Ishizuka, due Fang, not J., risk Han, melanoma S.N., with Stacey, Differentiation. association M.H., Testis Law, for M.M., Required Iles, and RNA Cytosine-5 Body Mouse inhibits Chromatoid The selectively (2013). the Biol. al. acid of et Cell. V., Meclofenamic Component Mol. J. (2015). a Flores, of C., Is al. Cox, Targeting NSun2 S., et Blanco, Small-Molecule Methyltransferase H., S., Menon, Res. (2019c). Zhou, F., Tuorto, Acids S., al. S., Nucleic Hussain, Gong, ALKBH5. et J., over H., Li, m6A of Xu, Q., demethylation Li, Z., FTO 5- J., Dong, Cell Yan, mRNA Cancer Y., L., of Leukemia. Huang, Dong, Myeloid identification Acute Y., Genome-wide in Sheng, (2019b). Demethylase N6- FTO R. R., Oncogenic RNA Zhang, Su, of and Y., at Biol. N., Huang, Recognition trimethylation Mol. Gu, H3 Struct. (2018). J., Histone Nat. (2019a). mammals. Liu, al. al. in W., methylcytosine et et Chen, M., H., Nature T., Sun, co-transcriptionally. B.S., Wu, Huang, modification Zhao, RNA H., T., m6A Wu, guides Shi, K., 36 Zhou, lysine X., H., Biol. Weng, Cell Qin, H., Nat. translation. Huang, W., and stability mRNA Sun, binding enhances N6-methyladenosine proteins H., an IGF2BP is by Weng, methyladenosine Ythdc2 (2017). H., al. et Res. Y., Huang, Cell Liu, spermatogenesis. X., 6 mammalian Shi, m Y., regulates Guo, that destabilizes H., protein Ma, YTHDF2 Y., (2020). Zhu, RNA P.J., C.J. cells. Hsu, stem Wilusz, pluripotent and induced protein– in E.O., EED differentiation Nishimura, restrain The 755. to J., (2017). RNAs Wilusz, al. neural-specific Biol. et J., A-modified Chem. K.M., Russo, Nat. Comess, complex. A.M., H., PRC2 Heck, Zhu, the C.G., inactivates Jakob, A-395 DNA inhibitor M.L., and interaction Curtin, histone protein S., of Selvaraju, modulators Y., molecule small He, Epigenetic Biol. (2018). Chem. M. Opin. Jung, Curr. and methylation. D., Cancer Robaa, Mol. prolifera- A.-T., manner. tumour Hauser, m6A-dependent promote METTL3 in (2019b). maturation al. pri-miR221/222 controlled et immunity accelerating H.-C., by Anti-tumour Lu, 18 R., cancer (2019a). Zhou, bladder al. H., of Yu, et X., tion Nature R., Yang, cells. J., Chang, Wang, dendritic Y., J., in Han, Liu, YTHDF1 L., and Dong, methylation m6A C., mRNA Chen, through J., Liu, D., Deciphering Biol. Han, (2019). Chem. al. Synthases. Ferr´e-D’Amar´e, et Pseudouridine and (2006). S., Cell T., Viukov, A.R. Profiling. Hamma, R., Quantitative Shachar, Antibody-Independent M., via Safra, Code” U., “m6A Toth, the S., epigenetic Edelheit, of Epigenetics timeline M.A., The Clin. Garcia-Campos, (2019). dreams. M. to Berdasco, R. reality and Trans. from C., Philos. discovery: Jeronimo, interference. M.G., drug Rots, cofactor P.B., Arimondo, for A., story Ganesan, success a Sci. discovery: Biol. drug B Soc. Epigenetic (2018). A. Ganesan, Oncogene ADAR2-editing axis. (2013). CDC14B/Skp2/p21/p27 al. the et of M., modulation Pezzullo, the M., 32 through Lezzerini, growth L., glioblastoma Cifaldi, inhibits S., activity Tomaselli, C., Rossetti, F., Galeano, 110. : 998–1009. : 33 373 1561–1570. : 20170069. : 45 73–85. : 18 26 380–388. : 11 174. : 45 27 43 2–2 432e1. 428–32, : 1115–1127. : 373–384. : 567 35 178 414–419. : 566 677-691.e10. : 731-747.e16. : 270–274. : 565 13 13 43–48. : 389–395. : 1125–1135. : 20 285–295. : 26 739– : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. i,X,Ca,G,W,Y,L,J,Ce,F,Lu . ta.(09.RAmAmtyainrgltsthe regulates methylation m6A Single- (2015). RNA Methods S.R. Nat. Jaffrey, (2019). transcriptome. and the al. C.E., throughout Mason, m6Am et C., and m6A Meydan, J., Commun. of A.O., Nat. Liu, mapping Olarerin-George, nucleotide-resolution Snail. V, F., A. of Grozhik, Chen, translation B., and J., Linder, cells activity. Li, cancer TUTase Y., of Zcchc11 transition Wu, of mesenchymal G., epithelial inhibitors Acute Chai, in molecule Role X., small Oncogenic Lin, of an Identification Plays FTO (2015). (2017b). R.I. Biol. Cell al. Gregory, RNA Cancer et and Demethylase. C., Ythdf2 RNA S., Li, reader -Methyladenosine Lin, Z., m6A 6 Zuo, of N X., Suppression a Weng, (2018b). as R., Leukemia al. Su, Myeloid et H., M., Weng, Gogol, Z., Res. X.C., Li, Cell He, expansion. H., cell Shi, promotes stem NMR W., hematopoietic RNA Lett. Shao, noncoding promotes Cancer P., long carcinoma. Novel Qian, cell (2018a). Z., squamous al. esophageal Li, et in W., Yang, BPTF X., and Shi, NSUN2 C., via Reveals Zhou, progression Mapping M., tumour Cell Base-Resolution Luo, Mol. (2017a). J., Transcripts. Li, al. Y., et Mitochondrial-Encoded Li, J., and Zhou, Nuclear- Y., in Chen, reveals Methylome K., mapping Wang, m1A Transcriptome-wide M., (2016b). Distinct Zhang, al. X., et Xiong, Biol. X., S., Chem. Li, Ma, Nat. X., methylome. Shu, N1-methyladenosine L., dynamic Wang, Enzymes Repair and K., Wang, AlkB reversible Chem. Inhibits X., Biol. Rhein Xiong, J. (2016a). X., Damage. C.-G. Li, Yang, DNA and Methylated H., to Chen, J., Cells Gan, Sensitizes X., and Liu, Y., Huang, Q., Li, Chem. H. Kaniskan, immune- in Chem. therapy Epigenetic (2019). H. ADAR1 De Kaniskan, D.D. (2013b). Carvalho, al. Cancer and Sci. Rev. et A., Nat. Acad. Chakravarthy, oncology. J.M., H., Natl. Isquith, Ohtani, Proc. P.A., A.C., leukemia. Jones, Court, myeloid chronic H.-J., ADAR1 in Chun, (2013a). reprogramming C.L., 1041–1046. al. progenitor Barrett, Sci. et malignant L.A., Acad. J.M., promotes Crews, Natl. Isquith, Q., Proc. A.C., leukemia. Jiang, Court, myeloid H.-J., chronic RNA in Chun, nuclear reprogramming C.L., in 1041–1046. N6-Methyladenosine progenitor Barrett, (2011). malignant Biol. L.A., al. Chem. promotes et Crews, Nat. Y., FTO. Q., Yang, obesity-associated G., Jiang, the Zheng, adaptive of Q., substrate stress Dai, major a X., a drive Zhao, is (2019). Y., to Fu, al. ribosomes G., et targets Jia, M, glioma Soler Neuropathol. in Mart´ınez-Card´us Llin`as-Arias P, Acta NSUN5 MC, program. A, RNA-methyltransferase translational Moura of de loss V, Epigenetic Dis. Ortiz-Barahona Death M, Cell export Janin apoptosis. nuclear TRAIL-induced by during activity caspase-3 PUS10 of protein, amplification RNA-modifying e3093–e3093. Reciprocal human (2017). a putative R. tumours: a Gupta, solid of and advanced A.C., and Hsieh, S., lymphoma Oncol. Jana, non-Hodgkin Lancet Tazemetostat, study. B-cell (2018). 1 refractory al. phase et or A., open-label, relapsed Varga, first-in-human, C., in Lucchesi, inhibitor, J.-M., EZH2 Michot, M., an Toulmonde, J.-C., Soria, A., Italiano, 58 58 1596–629. : 1596–629. : 12 . oz,KD,adJn .(05) eetv niioso rti ehlrnfrss .Med. J. methyltransferases. protein of inhibitors Selective (2015b). J. Jin, and K.D., Konze, U., . oz,KD,adJn .(05) eetv niioso rti ehlrnfrss .Med. J. methyltransferases. protein of inhibitors Selective (2015a). J. Jin, and K.D., Konze, U., ¨ ¨ 792–800. : 19 151–161. : 138 :1053-1074. 19 28 19 904–917. : 649–659. : 291 7 11083–11093. : 885–887. : 12 311–316. : 31 127–141. : 68 10 993-1005.e9. : 2065. : 12 430 767–772. : 57–66. : 110 110 8 : : : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. t,H,Skri . ut,R,Vlne . uff .E,Aioh,K,e l 21) DR Forms ADAR1 Cell (2013). Silencing. al. Gene et RNA-Induced K., and Ariyoshi, Processing B.-E., MicroRNA Wulff, Promote L., to Valente, Dicer 575–589. R., with Gupta, Complex M., Modifying a Genet. Sakurai, tRNA PLoS H., (2014). Cells. HeLa Ota, al. in et 5-Fluorouracil H., to Konishi, Sensitivity F., Determine Yazama, e1004639. METTL1, K., Okada, and M., NSUN2 Glioblas- Hori, Enzymes, in M., Editing Fujiwara, RNA M., Inhibits Okamoto, on Pre-mRNA Acts B Chem. That Subunit Deaminase Biol. Receptor Adenosine J. Glutamate (2017b). to toma. H.A. Binding Hundley, (ADAR3) and 3 A., Glioblas- RNA Cohen-Gadol, in A., Editing Anderson, RNA E., Inhibits on Oakes, Cell Pre-mRNA Acts B That Chem. Mol. Subunit Deaminase Biol. Receptor Adenosine Rev. J. Glutamate (2017a). to toma. H.A. Nat. Binding Hundley, (ADAR3) and ADARs. 3 A., by RNA Cohen-Gadol, Cell A., RNAs Anderson, Mol. non-coding E., and Oakes, Rev. coding Nat. of editing ADARs. A-to-I by Biol. RNAs (2016b). non-coding K. and Nishikura, coding of editing A-to-I Biol. Chem. (2016a). of synthesis Med. K. and Design Nishikura, Bioorg. (2014). drugs. cancer al. anti-prostate et M., as Ueda, inhibitors Lett. Y., (PCA-1/ALKBH3) Takeuchi, Y., antigen-1 Itoh, cancer T., prostate Shimizu, M., Epitranscriptome: (Basel). Mabuchi, the Above S., Genes Nakao, Identity. (2018). S. Cell Dyskerin- Martino, Stem Novel and and C., (2010). Emiliani, Modifications M., al. RNA Bazzucchi, et C., G., Argentati, Res. F., Storci, Cancer Morena, P., Translation. mRNA Sansone, Defective in L., through Inactivation Rocchi, component Dyskerin p53 S., of RNA Mechanism (2006). Bertoni, Mediated telomerase M., al. Calienni, and et L., pseudo-uridylation Montanaro, D., RNA Santini, Pathol. J. C., ribosomal cancer. Ceccarelli, of breast S., level human Barbieri, the J., influences Clohessy, Comprehensive Cell expression M., (2012). Codons. Brigotti, S.R. Stop Jaffrey, near L., and and Montanaro, UTRs C.E., 3’ in Mason, Enrichment O., Reveals Methylation Elemento, mRNA metastatic P., of the Zumbo, Analysis suppresses Y., MicroRNA Saletore, METTL14 primary K.D., (2017). -methyladenosine-dependent Meyer, al. 6 et N F., Wang, modulating J., Hepatology by Yuan, processing. carcinoma F., Invest. hepatocellular Liu, Cancer C., of Carcinoma. Zhou, potential Squamous Expression F., Neck Gene Yang, and NSUN2 J., Transferase Head tRNA Ma, in High (2018). Prognosis K. neck Poor Holzmann, and with and head Q., Associated Xu, gene in Methylation is H., survival methyltransferase Zeng, RNA patient G., RNA Zhu, on m6A L., score Transfer Lu, activation of (2020). cell Value T J. Oncol. Prognostic of Townsend, Oral effect carcinoma. The and the squamous (2019). V.L., modifies expression L. Cannataro, mRNA Wang, S.G., NSUN2 Gaffney, and L., C., Monit. Lu, Sci. Li, Med. L., Adenocarcinoma. Jin, RNA Colon N6-methyladenosine-dependent in C., (2015). Regulators Li, T. Pan, T., methylation and Liu, M., mRNA Nature Parisien, interactions. m6A C., RNA–protein Cell He, (2018). regulate G., Nat. switches al. Zheng, cancer. structural et Q., endometrial Dai, K., of N., Yu, tumourigenicity Liu, Z., and Lu, proliferation the S.-M., promote Liu, Biol. to B.T., activity Harada, AKT M.A., regulates Eckert, J., Liu, 20 17 17 24 1074–1083. : 83–96. : 83–96. : 1071–1074. : 292 292 65 4326–4335. : 4326–4335. : 529–543. : 210 101 10–18. : 104554. : 20 25 9435–9445. : 9 329. : 518 560–564. : 149 36 70 1635–1646. : 4767–4777. : 246–253. : 153 10 : : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. dnsn-oioiemR455 dtn rmtsmlnm rwhadmtsai.Nt elBiol. Reduced Cell (2015). Nat. al. et metastasis. M.E., and Vasquez, growth L., and melanoma Huang, translation T., promotes 311–321. facilitates Kamiya, YTHDF3 editing R.R., miR-455-5p (2017). Braeuer, adenosine-to-inosine al. A.K., et Mobley, P.J., E., Hsu, Shoshan, H., Res. Ma, Cell B.S., RNA. Zhao, N6-methyladenosine-modified microcephaly. Z., of and Lu, decay disability X., Wang, intellectual H., cause Shi, (2019). and al. humans et A.M., in Genet. Alazami, pseudouridylation I.S.M., Hum. Sayed, impair G.M.H., mutations Abdel-Salam, al. S., PUS7 et Maddirevula, M., m1A B.X., Tasak, R., The Leon-Ricardo, Shaheen, R.H., (2017). Herbst, ncRNA of Cell M., al. Pseudouridylation mRNA. Jovanovic, Dynamic-Regulated et and Widespread M.R., Reveals D., Mapping Mumbach, Bar-Yaacov, Transcriptome-wide Nature D.A., (2014). A., resolution. mediates Bernstein, Nachshon, single-base YTHDC1 S., R., at Schwartz, mRNA (2017b). Winkler, mitochondrial R., and al. cytosolic Nir, et on Y., A., landscape Cui, Sas-Chen, T., M., Elife Zhou, gene Safra, mRNAs. X., posttranscriptional methylated Wang, N6-methyladenosine for Z., of messages Zhang, export chemical G.-Z., nuclear — Luo, epigenetics I.A., Roundtree, RNA Biol. Chem. (2016). Opin. C. Curr. He, regulation. Expression and Gene in I.A., Modifications RNA Roundtree, Dynamic (2017a). C. He, Cell and T., Hema- Regulation. Pan, and M.E., Evans, Hematopoiesis I.A., in Roundtree, Epitranscriptomics Discov. RNA Cancer (2020). – Blood M. Esteller, synthases Malignancies. Biol. and tologic pseudouridine RNA G., Ferrer, stand-alone expression? Adenosine-to-Inosine M., gene Eukaryotic Rossello-Tortella, of (2014). regulators (2017). emerging al. Res. and U. et Cancer enzymes Kothe, H., modifying Carcinoma. Liu, and Cell F.-F., Squamous A.C., Li, Esophageal Rintala-Dempsey, in Y.-H., ADARs Zhu, by T.H.M., Mediated Clin. Chan, Editing J. J.-J., RNA E1905. Qiao, myeloid trial Y.-R., acute Intergroup Prolonged Qin, and Leukemia (2014). US syndrome the al. myelodysplastic of et for P.L., results entinostat Oncol. Greenberg, changes: without A., myelodysplasia-related Melnick, or with R., is with leukemia Ketterling, editing azacitidine M.E., RNA Biol. of Figueroa, A-to-I Genome administration Z., Massive reveals abundance. Sun, dsRNA RNA (2017). T., with E.Y. Prebet, hyper-edited correlates Levanon, and of and Metazoa map E., the genome-wide across Eisenberg, common A B.A., Knisbacher, and H.T., (2014). Dyskerin Porath, E.Y. Commun. (2015). Levanon, Nat. al. and sites. et new S., numerous Oncotarget G., Carmi, Bellezza, patients. H.T., cancer J., lung Vannucci, Porath, in A., survival Siggillino, in condition D., Pseudouridylation may Trere, expression RNA A (Basel). TERC V., 6 (2017). Genes Ludovini, m L. Worse. M., snRNA Montanaro, for Penzo, U6 and and The Better D., For Trere, (2017). Medicine: F., al. and Zacchini, et Physiology A.N., B.P., Tu, Guerrieri, Cell Y., M., Retention. Xie, Penzo, Intron V., Synthetase O. SAM Hunter, the Regulates Targeting K., METTL16 Cell Liu, Methyltransferase (2019). Leukemia. B., Myeloid Chen, al. Acute K.E., et in Pendleton, I., Cells Ivanova, Stem A., Cancer Shmakova, Compromises G.J., Cell Selectively Stem Spencer, YTHDF2 J., Reader m6A Campos, RNA M., Morgan, J., Paris, 32 25 1242–8. : 137-148.e6. : 138 169 159 231–239. : 1187–1200. : 148–162. : 5 30 4726. : 46–51. : 1 26–31. : 21 27 315–328. : 6 :. 8 :. 14 6 1185–1196. : 21755–21760. : 169 551 18 824-835.e14. : 185. : 251–255. : 74 840–851. : 17 : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. u .. ikrn,BF,Ceg . acr,S,Nue,D,Mnea . ta.(07.TeN6- The (2017). al. et G., Minuesa, D., Nguyen, hematopoietic S., Med. normal Nat. of Zaccara, cells. differentiation myeloid leukemia Y., controls and METTL3 Cheng, enzyme B.F., (m6A)-forming methyladenosine Pickering, L.P., Vu, Immunol. Trends munotherapy. Soc. Adenosine Chem. RNA-Editing Am. L., an J. cytosine Villanueva, for Design. RNA Analogues Inhibitor Substrate and Biol. (2012). (2003). Investigation P.A. Mol. Mechanistic al. Beal, Deaminase: Struct. and et Nat. L.M., S., synthesis. Easterwood, Kellner, V´eliz, protein E.A., S., and stability Hofmann, tRNA M., promotes Schaefer, of NSun2 19 and T., as Modulation Dnmt2 Musch, role by emerging R., methylation (2015). its Liebers, and RNA 5-methylcytosine F., al. Rev. modification Tuorto, et RNA Interdiscip. V.A., dynamic Wiley The Biol. Polito, mark. Genome (2019). epitranscriptomic S., A. an glioblastoma. Lusser, Galardi, in and deaminase S., L., ADAR2 -methyladenosineTrixl, based Raho, by 6 strategy processing S., and A N Alon, expression of editing, (2015). F., microRNA inhibitor Galeano, al. cell-active et S., and C.W.Q., Tomaselli, subfamily-selective Tang, a J.J.A., Sci. Low, to Chem. J., FTO. leads demethylase Tan, specificity L.Z.M., nucleotide Lau, catalyzes ADARB1 on L., Genet. (2017). Sun, Nat. senescence al. J.D.W., replicative rhythm. et Toh, delays RNA S., Kuroda, regulates NSun2 S., and Shimba, (2015). editing Y., NY). A-to-I al. Suzuki, (Albany. H., circadian et Aging Ozaki, Y., H., translation. Yoshitane, Dou, CDK1 H., B., elevating Terajima, and Jiang, helicase HIF-1 translation Z., RNA (KIP1) which Liu, p27 (2016). J., by repressing al. Xing, by efficiency X., et the Fan, J., H., of Tang, Konno, enhancement H., the Ikeda, epitranscriptome Lett. via Cancer K., The metastasis Takai, Oncol. (2017). translated. J. cancer M., al. Int. promotes et Tsunetomi, cells. T., YTHDC2 cancer K., Tanikawa, pancreatic Satoh, RNA-Modifying in M., A., Study radioresistance Toratani, Tanabe, and to J., chemo- Tool Koseki, promotes A., METTL3 a writer Asai, as m6A M., Aptamers Konno, Anti- RNA K., Exhibits Taketo, Fluorescent R-2HG (2016). (2018). Biol. al. S.R. Chem. et Cell Jaffrey, Enzymes. Y., and Qing, N., M., Wunderlich, Svensen, Cell S., Signaling. FTO/m6A/MYC/CEBPA Nachtergaele, Targeting C., by Li, acute Activity The adult tumour L., (2018). in Dong, al. activity R., et clinical Su, M.R., modest Savona, has J.G., and Berdeja, methylation Blood R., H3K79 leukemia. Tibes, reduces pinometostat D.A., and inhibitor Rizzieri, structural DOT1L G., Synthesis, Garcia-Manero, eIF4E: E.M., factor Stein, Chem. PUS10 initiation Med. human translation J. of the Eur. roles of characterisation. Differential functional inhibitors (2020). non-nucleotide al. and P et Biol. mimetic A., B., Bastide, Chem. M.W., Xie, Nowicki, Nat. F., B., Soukarieh, pseudouridylation. Lu, tRNA H., and Meng, processing C., miRNA Zhu, in Y., Zhuang, J., Song, ldz . n ie,M 21) tutrlisgt notemlclrmcaimo h 6 rtrcomplex. writer m6A the of mechanism molecular overexpression the DKC1 into insights (2009). Elife Structural al. Cancer (2016). et M. J. M., Jinek, Br. Sled´z, and Muller, P., A., progression. Wlazlinski, cancer R., prostate Engers, with J., associated Hatina, C., Hader, P., Sieron, ´ 900–905. : 5 :. lae-rio . n selr .(00.TeCnrbto fEieeist acrIm- Cancer to Epigenetics of Contribution The (2020). M. Esteller, and D., Alvarez-Errico, ´ 131 2661–2669. : 376 23 34–42. : 23 415–425. : 6 41 112–122. : 1369–1376. : 676–691. : yy . oe,C,Ddk . ta.(06.Dsg fnucleotide- of Design (2016). al. et K., Dudek, C., Jones, T., ¨ oyry, 124 200–217. : 22 10 101 e1510. : 1410–1416. : 49 146–151. : 16 172 160–169. : 90-105.e23. : 125 10867–10876. : 7 1143–1155. : α RAis mRNA 16 5. : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ho . atn .. ai,SL,Foec,B,Ae,SJ,adSajad ..(04.Rglto of Regulation (2004). R.A. Spanjaard, Steroid and of Modification S.J., Single-base Cell Posttranscriptional Mol. Ames, (2019). through Activator. Synthase B., al. RNA Pseudouridine Florence, Receptor a et by S.L., Z., Activity Davis, Adv. Receptor Zhang, J.R., Sci. Nuclear I.A., method. Patton, Roundtree, antibody-independent X., ALKBH5 an C.-G., Demethylase Zhao, by Yang, A A Y.-L., 6 6 m m Zhao, of (2017c). L.-Q., mapping al. I Chen, et type Z., Pro- Z., by Cell Zhang, Lu, induced and Expression S., is FOXM1 Cell Zheng, editing Sustaining Cancer by K., RNA Program. Cells Lin, liferation (2017b). Stem-like A., Glioblastoma J. of Zhou, He, Tumourigenicity B.S., Maintains and Zhao, X., Biol. S., Hu, Tumour Zhang, carcinoma. J., cell Huang, squamous NANOG Z., esophageal of Tang, in A-demethylation Z., interferon breast the 6 Chen, induces m J., Hypoxia ALKBH5-mediated Zhang, (2016). al. and Sci. et Acad. HIF-dependent I., Natl. haematopoietic Chen, by Proc. H., modulates phenotype mRNA. Zhang, m6A J.W., cell (2017a). Bullen, stem al. H., et cancer Lu, D., D., Samanta, Ma, C., Y., Zhang, Nature Yang, specification. L., Res. cell Wang, Cell progenitor B., reader. and m5C Sun, an stem Y., as promotes FTO Chen, ALYREF 5-methylcytosine demethylase (2017b). C., and al. methyltransferase mRNA Zhang, et the m6A W.-Y., as Lai, (2019). NSUN2 J.-W., al. Xu, — Y.-S., export et Chen, mRNA Commun. B.-F., Y., Sun, methyl- Nat. Deng, Y., blockade. Yang, tRNA P., anti-PD-1 X., Yang, of Shah, to G., Association response Park, and (2017a). tumourigenicity Y.-H., L. melanoma Cui, Lu, regulates J., Oncol. and Futur. Wei, H., survival. the S., cancer Huang, Promotes Yang, ovarian C., METTL3 with Huang, (2020). signature M., molecular al. NSUN2/IGF-II Zhang, et transferase Oncol. E., Y., Front. Pathway. Wang, Risch, MYC N6-methyladenosine Q.-N., J., the Wu, dynamic Yang, Targeting via A J.-H., via (2018). Lu, Growth Cancer Gastric al. K., Cell of Yu, et Promotes Res. Progression Z.-H., N., Cell NSun2 Zhao, Chen, inhibitors. (2015). kinase J., D.-D., tyrosine Yang, Pang, al. to J., resistance et acquired Liu, X., and Z., intrinsic Zhang, regulates Zhang, methylome Z., A., Al-Kali, Liu, Biol. F., Reader H., Cell. Yan, A Tang, Mol. 6 Translation. X., m 1 Nuclear Cai, Kinase (2016). Cyclin-Dependent J., al. Elevating et Yi, B.-F., J., Sun, Xing, Mech. Y.-J., Cell Hao, Regul. Mol. Y.-S., Splicing. Gene Chen, mRNA - U., Regulates Dahal, Acta YTHDC1 S., Biophys. Adhikari, Biochim. W., Xiao, cells. cancer CSF-1 ovarian the and increases demethylation breast 35–46. m1A in ALKBH3-induced Human stability Stem (2019). mRNA S.K. Cell Chambers, and Modification. H.-H., Hematopoietic m6A Woo, Inhibits METTL14 mRNA (2018). via al. et Leukemogenesis N6-methyladenosine-dependent L., Dong, Promotes (2014). Cell B.S., and al. Zhao, X., Differentiation et Qin, D., Stem/Progenitor H., Wu, Han, H., Huang, Y., H., Yue, Weng, Nature G.C., stability. Hon, RNA A., messenger Soc. of Gomez, Chem. regulation Z., Am. Lu, J. Protein. X., Wang, FTO Bifunctional of as Derivatives Labeling Fluorescein and (2015). al. Inhibiting et 13739. Y., Simultaneous Chen, the F., Wu, Malignant for H., on Su, Molecules Regulators Oncol. Y., Methylation Front. Huang, RNA T., Carcinoma. Hong, m6A Cell T., of Wang, Clear Effect Renal (2020). in X. Gou, Prognosis and and W., Progression He, C., Zhang, J., Wang, 22 191-205.e9. : 113 31 591-606.e6. : E2047–E2056. : 15 549–558. : 549 505 61 273–276. : 507–519. : 117–120. : 23 39 5 35 101042831770854. : eaax0250. : 4043–4052. : 10 :. 10 :. 10 13 28 2782. : 27 137 1981–1990. : 1062–1076. : 606–625. : 13736– : 1862 : Posted on Authorea 9 Nov 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160495480.00891340/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. druggable-epitranscriptome-compounds-that-target-rna-modifications-in-cancer 2.pdf Table file Hosted druggable-epitranscriptome-compounds-that-target-rna-modifications-in-cancer 1.pdf Table file Hosted druggable-epitranscriptome-compounds-that-target-rna-modifications-in-cancer 2.pptx Figure file Hosted druggable-epitranscriptome-compounds-that-target-rna-modifications-in-cancer 1.pptx Quimatryx. Figure and Ferrer of consultant is file M.E. Hosted interest. of conflicts no discloses MB STATEMENT INTEREST OF RTI2018- ME CONFLICT (LCF/PR/GN18/51140001). no. Foundation Professor. project Banking Research Caixa” ICREA (ERDF) “la an Fund Foundation; is Development Agencia Innovaci´on Cellex Regional (MCI), Funds e the Ciencia and Development European 2017SGR1080 de 094049-B-I00 supported and Regional Ministerio Investigaci´on labis no. (AEI) Catalunya); European M.E. AGAUR-projects de de M.B. at and by (Generalitat Estatal SLT/002/16/00374 Research Government at co-funded Catalan no. PI18/00910). Research the III PERIS-project and of Department Carlos (PI15/00638 Health Europe Salud support. the build de by institutional to Instituto way for a by Catalunya (ERDF/FEDER) supported de is Programme/Generalitat lab CERCA thank We manuscript. the of FUNDING aspects all to contributed authors All CONTRIBUTIONS AUTHOR modification. the m6A, with 2. together cytidine; Figure listed 5-methyl are m5C, modification N1-methyladenosine; writers RNA m1A, known each edition; N6-methyladenosine. The for Adenosine-to-Inosine illustrated. (R) I, are readers pseudouridine; edition and adenosine-to-inosine (E) erasers and (W), pseudouridylation nucleosides, at tion (2016). 1 al. Figure et H.-J., Chun, LEGENDS L., Cell FIGURE Stem Balaian, Cell Biogenesis. N.P., Let-7 Santos, of Impairing by Regulation Delos 177–191. Self-Renewal Clock : Cell A., Stem Circadian Leukemia and Sadarangani, (2018). Drives Rep. Functions Activation A.C., al. ADAR1 Cell et Multiple Court, Methylation. C.M., mRNA (2019). M.A., Cham, m6A al. Zipeto, Y., of Li, et Modulation X., by M., Weng, Metabolism Zhang, K., Lipid Oncol. Frazier, Hepatic Front. H., J., Cancers. Yu, Jiang, Human X., S., in Zhong, METTL3 Wang, of Y., Role Zhao, the Underlying Mammalian X., Cell Mechanisms a Mol. Dong, Is Fertility. ALKBH5 Mouse W., (2013). and al. 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