The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 21, 2021

Abstract N 6 -methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher cells. m6A modified by methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, KIAA1429, and, removed demethylases, erasers, including FTO ALKBH5. It recognized m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 HNRNPA2B1, also known “readers”. Recent studies have shown that RNA plays essential role both physiological pathological conditions, initiation progression of different types human cancers. In this review, we discuss how methylation influences progressions hematopoietic, central nervous reproductive systems. We will mainly focus on recent progress identifying biological functions underlying molecular mechanisms methylation, its regulators downstream target genes, during cancer above propose process offer potential targets for therapy future.

Language: Английский

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Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: May 31, 2021

Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since first tyrosine kinase inhibitor imatinib was approved enter market by US Food Drug Administration (FDA) 2001, an increasing number of small-molecule been developed for treatment malignancies. By December 2020, 89 antitumor FDA National Medical Products (NMPA) China. Despite great progress, anti-cancer still face many challenges, such as a low response rate drug resistance. To better promote development we conducted comprehensive review according target classification. We present all well important candidates clinical trials each target, discuss current provide insights perspectives research drugs.

Language: Английский

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Functions of N6-methyladenosine and its role in cancer

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: Dec. 1, 2019

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A installed by methyltransferases, removed demethylases recognized reader proteins, regulate RNA metabolism including translation, splicing, export, degradation microRNA processing. Alteration levels participates cancer pathogenesis development via expression tumor-related genes like BRD4, MYC, SOCS2 EGFR. In this review, we elaborate recent advances research enzymes. We also highlight underlying mechanism progression. Finally, review corresponding potential targets therapy.

Language: Английский

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Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution

Molecular Cell, Journal Year: 2019, Volume and Issue: 76(2), P. 329 - 345

Published: Oct. 1, 2019

Language: Английский

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A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA

Cell, Journal Year: 2020, Volume and Issue: 181(7), P. 1582 - 1595.e18

Published: June 1, 2020

N6-methyladenosine (m6A) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology differentiation. m6A thought to mediate its effects through a complex network interactions between different sites three functionally distinct cytoplasmic YTHDF m6A-binding proteins (DF1, DF2, DF3). In contrast prevailing model, we show that DF bind same m6A-modified mRNAs rather than mRNAs. Furthermore, find do not induce translation in HeLa cells. Instead, paralogs act redundantly degradation The ability regulate stability differentiation becomes evident only when all are depleted simultaneously. Our study reveals unified model function which subjected combined action proportion number sites.

Language: Английский

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ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(33), P. 20159 - 20170

Published: Aug. 3, 2020

Significance N 6 -methylation of adenosine (m A) RNA modification plays important roles in development and tumorigenesis. The functions mechanisms m A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma colon syngeneic mouse models to study the ALKBH5 FTO anti–PD-1 antibody GVAX vaccination therapy. We found that knockout tumor cells enhances efficacy prolonged survival. modulates target gene expression splicing, leading changes metabolite contents, such as lactate microenvironment, which regulates suppressive lymphocytes Treg myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, observed similar phenotype, indicating future translational application our findings.

Language: Английский

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The emerging role of RNA modifications in the regulation of mRNA stability

Experimental & Molecular Medicine, Journal Year: 2020, Volume and Issue: 52(3), P. 400 - 408

Published: March 1, 2020

Many studies have highlighted the importance of tight regulation mRNA stability in control gene expression. largely depends on nucleotide sequence, which affects secondary and tertiary structures mRNAs, accessibility various RNA-binding proteins to mRNAs. Recent advances high-throughput RNA-sequencing techniques resulted elucidation important roles played by modifications sequences regulating stability. To date, hundreds different RNA been characterized. Among them, several modifications, including N

Language: Английский

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The evolving metabolic landscape of chromatin biology and epigenetics

Nature Reviews Genetics, Journal Year: 2020, Volume and Issue: 21(12), P. 737 - 753

Published: Sept. 9, 2020

Language: Английский

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A comprehensive review of m6A/m6Am RNA methyltransferase structures

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 49(13), P. 7239 - 7255

Published: April 26, 2021

Abstract Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression control via has been termed ‘epitranscriptomics’ keep with the related ‘epigenomics’ for DNA modification. One such modification N6-methylation found adenosine (m6A) 2′-O-methyladenosine (m6Am) in most types of RNA. The can affect fold, stability, degradation cellular interaction(s) modified RNA, implicating it processes as splicing, translation, export decay. multiple roles played by this explains why m6A misregulation connected human cancers. m6A/m6Am writer enzymes methyltransferases (MTases). Structures available functionally characterized MTases from (m6A mRNA, snRNA, rRNA m6Am mRNA MTases), zebrafish (m6Am MTase) bacteria MTase). For each these MTases, we describe their overall domain organization, active site architecture substrate binding. We identify areas that remain be investigated, propose yet unexplored routes structural characterization MTase:substrate complexes, highlight common elements should described future MTase structures.

Language: Английский

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Molecular Mechanisms Driving mRNA Degradation by m6A Modification

Trends in Genetics, Journal Year: 2020, Volume and Issue: 36(3), P. 177 - 188

Published: Jan. 18, 2020

N6-Methyladenosine (m6A) as an mRNA modification plays multiple roles in various steps/characteristics of processing and metabolism, such splicing, export, translation, stability.YTHDF2 preferentially recognizes m6A recruits RNA-degrading enzymes or adaptor proteins to trigger rapid degradation the m6A-containing mRNA.Depending on presence HRSP12-binding sites mRNAs, YTHDF2 elicits one two RNA decay pathways: deadenylation by YTHDF2–CCR4/NOT deadenylase complex endoribonucleolytic cleavage via YTHDF2–HRSP12–RNase P/MRP complex.The stability mRNAs is regulated dynamic crosstalk between other cellular factors, RNA-binding proteins, structures, and/or types modification. (m6A), most prevalent internal associated with eukaryotic influences many steps including well stability. Recent studies have revealed that undergo distinct pathways degradation: YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; reader protein)–CCR4/NOT (deadenylase) YTHDF2–HRSP12–ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some circular RNAs (circRNAs) are also subject P/MRP. Here, we highlight recent progress molecular mechanisms underlying describe our current understanding regulation m6A-mediated through (or YTHDF2) factors. Many point role a mode post-transcriptional gene this field has been termed 'epitranscriptomics' [1.Roundtree I.A. et al.Dynamic modifications expression regulation.Cell. 2017; 169: 1187-1200Abstract Full Text PDF PubMed Scopus (836) Google Scholar, 2.Kadumuri R.V. Janga S.C. Epitranscriptomic code its alterations human disease.Trends Mol. Med. 2018; 24: 886-903Abstract (49) 3.Esteller M. Pandolfi P.P. The epitranscriptome noncoding cancer.Cancer Discov. 7: 359-368Crossref (78) 4.Meyer K.D. al.Comprehensive analysis methylation reveals enrichment 3′ UTRs near stop codons.Cell. 2012; 149: 1635-1646Abstract (1634) Scholar]. To date, approximately 150 species, tRNAs, rRNAs, (ncRNAs), viral genomes [5.Helm Motorin Y. Detecting epitranscriptome: predict validate.Nat. Rev. Genet. 18: 275-291Crossref (249) 6.Boccaletto P. al.MODOMICS: database pathways. 2017 update.Nucleic Acids Res. 46: D303-D307Crossref (654) 7.Nachtergaele S. He C. Chemical life transcript.Annu. 52: 349-372Crossref (66) In review, summarize reports deposition function. particular, discuss findings regarding how contributes at level. Although first discovered 1970s, recently returned spotlight development RNA-seq techniques characterization involved [4.Meyer Scholar,8.Dominissini D. al.Topology mouse methylomes m6A-seq.Nature. 485: 201-206Crossref (1829) This found expressed mammalian cell blood, muscle, liver, intestinal, neuronal cells. At level, functions almost all stages cycle, regulates (Figure 1). implicated variety physiological events spermatogenesis [9.Lin Z. al.Mettl3-/Mettl14-mediated N6-methyladenosine modulates murine spermatogenesis.Cell 27: 1216-1230Crossref (119) Scholar], embryogenesis [10.Wang al.N6-methyladenosine embryonic neural stem self-renewal histone modifications.Nat. Neurosci. 21: 195-206Crossref (125) cortical neurogenesis [11.Yoon K.J. al.Temporal control methylation.Cell. 171: 877-889.e817Abstract (266) carcinogenesis [12.Barbieri I. al.Promoter-bound METTL3 maintains myeloid leukaemia m6A-dependent translation control.Nature. 552: 126-131Crossref (366) 13.Choe J. al.mRNA circularization METTL3-eIF3h enhances promotes oncogenesis.Nature. 561: 556-560Crossref (191) 14.Lin al.The methyltransferase cancer cells.Mol. Cell. 2016; 62: 335-345Abstract (559) As modification, 25% harbor more bases general, enriched around codons untranslated region (UTR) Scholar,15.Linder B. al.Single-nucleotide-resolution mapping m6Am throughout transcriptome.Nat. Methods. 2015; 12: 767-772Crossref (590) although varies among different mRNAs. Accumulating evidence indicates reversible event coordinated action methyltransferases (m6A writers) demethylases erasers) depletion Methyltransferase-like 3 (METTL3) (see Glossary), known MT-A70, METTL14 function catalytic core m6A–METTL (MAC). DRACH motif (where D = A, G, U; R purine; H C, U) introduces into nascent transcripts Notably, activity, whereas forms heterodimer binding target [16.Scholler E. al.Interactions, localization, phosphorylation generating METTL3–METTL14–WTAP complex.RNA. 499-512Crossref (118) 17.Sledz Jinek Structural insights mechanism writer complex.eLife. 5e18434Crossref (195) 18.Wang al.Structural basis for cooperative Mettl3 Mettl14 methyltransferases.Mol. 63: 306-317Abstract (341) activity MAC conjunction regulatory – m6A–METTL-associated (MACOM) comprising Wilms tumor 1-associated (WTAP) (also female-lethal[2]d), 15 (RBM15), Vir-like methyltransferase-associated (VIRMA) Virilizer KIAA1429), Cbl proto-oncogene-like 1 (CBLL1) Hakai), zinc-finger CCCH-type-containing 13 (ZC3H13) [19.Lence T. al.Mechanistic enzymes.Biochim. Biophys. Acta. 2019; 1862: 222-229Crossref (37) MACOM itself lacks interaction components localization specific RBM15 paralog RBM15B interact WTAP-dependent manner bind U-rich sequences [20.Patil D.P. al.m6A XIST-mediated transcriptional repression.Nature. 537: 369-373Crossref (572) Scholar,21.Knuckles al.Zc3h13/Flacc required adenosine bridging mRNA-binding factor Rbm15/Spenito machinery component Wtap/Fl(2)d.Genes Dev. 32: 415-429Crossref (170) result, recruit MAC–WTAP proximal consensus motifs. It suggested VIRMA mediates participates alternative polyadenylation association CFIm (a tetramer CPSF5 CPSF6) RNA-dependent [22.Yue al.VIRMA preferential 3′UTR codon associates polyadenylation.Cell 4: 10Crossref (223) Depletion induces lengthening, reduced amount By contrast, leads shortening 3′UTR, increased abundance codons. Considering defined cytoplasm, lengthening occurs nucleus, details VIRMA-mediated should be investigated future studies. ZC3H13 nuclear ZC3H13–WTAP–VIRMA–CBLL1 cells [23.Wen al.Zc3h13 self-renewal.Mol. 69: 1028-1038.e1026Abstract (242) serves adapter WTAP RBM15, enable efficient [21.Knuckles now established installed cotranscriptionally Scholar,24.Knuckles al.RNA fate determination cotranscriptional microprocessor binding.Nat. Struct. Biol. 561-569Crossref (72) 25.Ke deposited pre-mRNA not splicing but do specify cytoplasmic turnover.Genes 31: 990-1006Crossref (221) 26.Slobodin al.Transcription impacts efficiency co-transcriptional N6-adenosine 326-337.e312Abstract (182) CCAAT/enhancer-binding zeta (CEBPZ) binds transcription start site promoter independent METTL14, thereby inducing protein-coding recruited chromatin transcription-dependent methylates [24.Knuckles report showed conversion A m6As depends polymerase II. low rate elongation greater number transcript [26.Slobodin Furthermore, it majority formed exon chromatin-associated during [25.Ke possible reversibility was demonstrated identification demethylases: α-ketoglutarate-dependent dioxygenase alk B homolog 5 (ALKBH5) fat mass obesity-associated (FTO) [27.Jia G. al.N6-Methyladenosine major substrate FTO.Nat. Chem. 2011; 885-887Crossref (1512) Scholar,28.Zheng al.ALKBH5 demethylase metabolism fertility.Mol. 2013; 49: 18-29Abstract (1256) ALKBH5 demethylates motif-dependent manner, FTO broad spectrum substrates [28.Zheng Therefore, plausible than global demethylation. originally overweight obesity humans [29.Dina al.Variation childhood severe adult obesity.Nat. 2007; 39: 724-726Crossref (1129) Scholar,30.Frayling T.M. al.A common variant body index predisposes obesity.Science. 316: 889-894Crossref (2997) Later, shown demethylate polyadenylated Scholar,31.Fu al.FTO-mediated formation N6-hydroxymethyladenosine N6-formyladenosine RNA.Nat. Commun. 1798Crossref (208) several provided results upregulation total Scholar,32.Zhao X. al.FTO-dependent demethylation adipogenesis.Cell 2014; 1403-1419Crossref (459) suggest N6,2′-O-dimethyladenosine (m6Am), which adjacent 7-methylguanosine cap affects [33.Mauer al.Reversible 5′ controls stability.Nature. 541: 371-375Crossref (425) More recently, N1-methyladenosine (m1A) tRNAs [34.Wei al.Differential m6A, m6Am, m1A mediated nucleus cytoplasm.Mol. 71: 973-985.e975Abstract (193) gene-regulatory biological effects summarized review papers [35.Shi H. al.Where, when, how: context-dependent writers, readers, erasers.Mol. 74: 640-650Abstract (284) Scholar,36.Delaunay Frye regulating cancer.Nat. Cell 552-559Crossref (93) noted these involving mostly m6A-recognizing (RBPs) proteins), YTH (YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2), initiation 3, heterogeneous ribonucleoprotein (hnRNP) hnRNP hnRNPA2B1. decay. destabilization identified uncovered increase half-life after (METTL3 WTAP) downregulation both [37.Batista P.J. transition cells.Cell Stem 15: 707-719Abstract (549) 38.Schwartz al.Perturbation writers classes sites.Cell Rep. 8: 284-296Abstract (558) 39.Liu METTL3–METTL14 methylation.Nat. 10: 93-95Crossref (1090) Then, discovery m6A-specific structural they conserved across species [40.Li F. al.Structure domain mononucleotide aromatic cage recognition.Cell 1490-1492Crossref (109) Scholar,41.Zhu al.Crystal structure recognition N6-methyladenosine.Cell 1493-1496Crossref (131) became characterize 2, Key Figure). Thus far, seems three YTHDF 3) can work together destabilize same subset [42.Lu W. al.N6-Methyladenosine-binding suppress HIV-1 infectivity production.J. 293: 12992-13005Crossref 43.Shi al.YTHDF3 facilitates N6-methyladenosine-modified RNA.Cell 315-328Crossref (500) 44.Tirumuru N. infection Gag expression.eLife. 5e15528Crossref (138) Nonetheless, outlining behind seem consistently indicate decay-inducing [45.Du al.YTHDF2 destabilizes direct recruitment CCR4–NOT complex.Nat. 12626Crossref (407) Scholar,46.Park O.H. al.Endoribonucleolytic RNase complex.Mol. 494-507.e498Abstract (126) Growing shows responsible localizing from translating pools bodies (P bodies) [47.Wang al.N6-Methyladenosine-dependent messenger 505: 117-120Crossref (1457) Scholar,48.Ries R.J. phase separation potential mRNA.Nature. 571: 424-428Crossref (171) where participating [49.Luo al.P-bodies: composition, properties, functions.Biochemistry. 57: 2424-2431Crossref (120) Scholar,50.Sheth U. Parker R. Decapping occur bodies.Science. 2003; 300: 805-808Crossref (914) study that, under stress conditions, partitions intracellular phase-separated compartments, P bodies, granules, granules [48.Ries However, another research group reported directly CCR4/NOT independently components, triggering precedes [51.Zheng al.Deadenylation prerequisite P-body cells.J. 2008; 182: 89-101Crossref Scholar] exosome (3′-to-5′ exoribonuclease complex), engaged deadenylation, 50.Sheth 51.Zheng CCR4/NOT-mediated subsequent exosome-mediated 3′-to-5′ exoribonucleolytic may initiate outside bodies. remaining intermediate then decapping, followed 5′-to-3′ decapping (XRN1) An additional route YTHDF2-mediated [46.Park bound associate P/MRP, endoribonuclease (Box bridged protein: heat-responsive 12 (HRSP12) reactive imine deaminase homolog, UK114 antigen 14.5 kDa translational inhibitor protein). Experiments based crosslinking immunoprecipitation next-generation sequencing characterized HRSP12 new RBP preference sequence GGUUC. Of note, located half palindromic sequence, suggesting recognize stem–loop primary sequences. Besides serving adaptor, mRNA. Moreover, With help binding, eventually performs Currently, remains unknown whether endoribonucleolytic-cleavage bodies.Box 1Molecular Properties P/MRPRNase MRP RNP complexes humans, yeast, mice, flies [86.Jarrous Roles subunits.Trends 33: 594-603Abstract (27) endonuclease cleaves leader precursor form tRNAs. subunits combinatorial assembly give rise myriad complexes. cleave mitochondrial (hence name), mitochondria widely nuclease 5.8S rRNA processing. share least seven (POP1, POP5, RPP20, RPP25, RPP30, RPP38, RPP40) similar secondary tertiary structures. Other distinguished their unique ncRNA components: RPPH1 RMRP RNA, respectively.Targets limited tRNA, include long ncRNAs accumulate particular location CLB2 promote cycle progression. addition, viperin cleaved Park al. cytoplasm internally them respectively. Targets P/M

Language: Английский

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