METTL3 from Target Validation to the First Small-Molecule Inhibitors: A Medicinal Chemistry Journey

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(3), P. 1654 - 1677

Published: Jan. 24, 2023

RNA methylation is a critical mechanism for regulating the transcription and translation of specific sequences or eliminating unnecessary during maturation. METTL3, an methyltransferase that catalyzes transfer methyl group to N6-adenosine RNA, one key mediators this process. METTL3 dysregulation may result in emergence variety diseases ranging from cancer cardiovascular neurological disorders beyond contributing viral infections. Hence, discovery inhibitors assist furthering understanding biological roles enzyme, addition development novel therapeutics. Through work, we will examine existing correlations between diseases. We also analyze development, mode action, pharmacology, structure–activity relationships currently known inhibitors. They include both nucleoside non-nucleoside compounds, with latter comprising competitive allosteric

Language: Английский

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Physiological functions of RIG-I-like receptors

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 731 - 751

Published: April 1, 2024

Language: Английский

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Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: May 2, 2024

Abstract N6‐methyladenosine (m 6 A) modification, installed by METTL3‐METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role oral mucosal immunity remains ambiguous. Periodontitis a special but prevalent infectious disease characterized as hyperinflammation of mucosa bone resorption. Here, it reported that genetic deletion Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability TNFAIP3 (also known A20) transcript significantly attenuated upon m A modification. When silencing METTL3, accumulated functioning ubiquitin‐editing enzyme facilitates ubiquitination NEK7 [NIMA (never mitosis gene a)‐related kinase 7], subsequently impairs assembly. Furtherly, Coptisine chloride, natural small‐molecule, discovered novel METTL3 inhibitor performs therapeutic effect on periodontitis. The study unveils previously unknown pathogenic mechanism METTL3‐mediated modifications periodontitis indicates potential target.

Language: Английский

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Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 65(4), P. 2866 - 2879

Published: Sept. 27, 2021

The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify 2-phenyl-1,2-benzoselenazol-3-one class compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant Mpro identified six that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments molecular docking determined inhibition can occur by either covalent or noncovalent mechanisms, lead E04 was to competitively. Lead E24 inhibited viral replication EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells further confirmed impair human lung epithelial human-induced pluripotent stem cell-derived 3D organoids. Altogether, these studies provide structural framework mechanism should facilitate future treatments.

Language: Английский

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Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication

mBio, Journal Year: 2021, Volume and Issue: 12(4)

Published: July 6, 2021

The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing global public crisis. Although viral RNA modification has been reported based on the transcriptome architecture, types and functions of are still unknown. In this study, we evaluated roles N6-methyladenosine (m6A) in SARS-CoV-2. Our methylated immunoprecipitation sequencing (MeRIP-Seq) Nanopore direct (DRS) analysis showed that SARS-CoV-2 contained m6A modification. Moreover, infection not only increased expression methyltransferase-like 3 (METTL3) but also altered its distribution. Modification METTL3 short hairpin or plasmid transfection for knockdown overexpression, respectively, affected replication. Furthermore, key protein RdRp interacted with METTL3, was distributed both nucleus cytoplasm presence RdRp. appeared to modulate sumoylation ubiquitination via unknown mechanism. Taken together, our findings demonstrated host complex proteins IMPORTANCE Internal chemical modifications play regulation replication gene expression. potential internal have RNA, function life cycle unclear. current underwent machinery. pattern methyltransferases demethylases, while level fat mass obesity-associated (FTO) linked Further study polymerase RNA-dependent (RdRp), which influenced distribution posttranslational METTL3. provided evidence components

Language: Английский

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The detection and functions of RNA modification m6A based on m6A writers and erasers

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 297(2), P. 100973 - 100973

Published: July 16, 2021

N6-methyladenosine (m6A) is the most frequent chemical modification in eukaryotic mRNA and known to participate a variety of physiological processes, including cancer progression viral infection. The reversible dynamic m6A installed by methyltransferase (writer) enzymes erased demethylase (eraser) enzymes. recognized binding proteins (readers) regulates RNA processing metabolism, leading downstream biological effects such as promotion stability translation or increased degradation. writers erasers determine abundance modifications play decisive roles its distribution function. In this review, we focused on present an overview their functions enzymatic molecular mechanisms, showing how they recognize substrates install remove modifications. We also summarize current applications for detection highlight merits drawbacks these available methods. Lastly, describe cancers infection based research introduce new assays functionality via programmable editing tools. plays central role dogma biology responsible transmitting genetic information encoded DNA into functional proteins. There are different types molecules that involved regulation several messenger (mRNA), transfer (tRNA), ribosomal (rRNA), microRNA (miRNA), long noncoding (lncRNA), etc. Analogous histone (1Lewis J.D. Meehan R.R. Henzel W.J. Maurer-Fogy I. Bird A. Purification, sequence, cellular localization novel chromosomal protein binds methylated DNA.Cell. 1992; 69: 905-914Abstract Full Text PDF PubMed Scopus (1022) Google Scholar, 2Wang Y. Wysocka J. Perlin J.R. Leonelli L. Allis C.D. Coonrod S.A. Linking covalent epigenetics: rigidity plasticity marks.Cold Spring Harb. Symp. Quant. Biol. 2004; 161-169Crossref (0) Scholar), contain numerous (more than 150) (3Machnicka M.A. Milanowska K. Osman Oglou O. Purta E. Kurkowska M. Olchowik Januszewski W. Kalinowski S. Dunin-Horkawicz Rother K.M. MODOMICS: A database pathways—2013 update.Nucleic Acids Res. 2012; 41: D262-D267Crossref Scholar). Among them, N7-methylguanosine (m7G), (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), pseudouridine (Ψ), 2′-O-methylation (Nm), cap N6,2′-O-dimethyladenosine (m6Am), N4-acetylcytidine (Ac4C) have been identified mammalian (4Wei C.M. Gershowitz Moss B. Methylated nucleotides block 5' terminus HeLa cell RNA.Cell. 1975; 4: 379-386Abstract (392) 5Rottman F. Shatkin A.J. Perry R.P. Sequences containing at 5′ termini RNAs: Possible implications processing.Cell. 1974; 3: 197-199Abstract (166) All endogenous "writer" enzymes, methyltransferase. Some methylation can be reversibly removed "eraser" demethylases "reader" metabolism (6Jia G. Fu He C. Reversible adenosine regulation.Trends Genet. 2013; 29: 108-115Abstract (181) 7Zhang Jia (m1A) tRNA.Genomics Proteomics Bioinformatics. 2018; 16: 155-161Crossref (12) fast-expanding termed epitranscriptomics. abundant internal comprises approximately 0.1 0.4% all adenosines, there about 3 5 each average, mainly composed G(m6A)C (70%) A(m6A)C (30%) located nearby stop codon 3′ untranslated region (3′ UTR) (8Wei 5'-Terminal nucleotide sequences mRNA.Biochemistry. 1976; 15: 397-401Crossref 9Wei Nucleotide sites ribonucleic acid.Biochemistry. 1977; 1672-1676Crossref (145) existence was first reported from cells 1970s (10Desrosiers R. Friderici Rottman Identification nucleosides Novikoff hepatoma cells.Proc. Natl. Acad. Sci. U. 71: 3971-3975Crossref (711) demonstrating unique rRNA tRNA, which possess complex base-methylnucleoside patterns. 1990s, multisubunit addition methyl group onto nuclear extracts (11Bokar J.A. Rath-Shambaugh M.E. Ludwiczak Narayan P. Characterization partial purification N6-adenosine nuclei. Internal requires complex.J. Chem. 1994; 269: 17697-17704Abstract However, rarely due limitation advanced technology. widespread study reignited after discovery 2011—the fat obesity-associated (FTO) (12Jia G.F. Zhao X. Dai Q. Zheng G.Q. Yang Yi C.Q. Lindahl T. Pan Y.G. major substrate FTO.Nat. 2011; 7: 885-887Crossref (1550) indicates dynamically similar (5 mC) (13Ito D'Alessio A.C. Taranova O.V. Hong Sowers L.C. Zhang Role Tet 5mC 5hmC conversion, ES-cell self-renewal inner mass specification.Nature. 2010; 466: 1129-1133Crossref (1774) Development antibody-based transcriptomic sequencing methods paved way (14Dominissini D. Moshitch-Moshkovitz Schwartz Salmon-Divon Ungar Osenberg Cesarkas Jacob-Hirsch Amariglio N. Kupiec Sorek Rechavi Topology human mouse methylomes revealed m6A-seq.Nature. 485: 201-206Crossref (1879) 15Meyer K.D. Saletore Zumbo Elemento Mason C.E. Jaffrey S.R. Comprehensive analysis reveals enrichment UTRs near codons.Cell. 149: 1635-1646Abstract (1670) 16Chen Lu Z.K. Wang Luo G.Z. Liu Han D.L. Dominissini High-resolution map using photo-crosslinking-assisted sequencing.Angew. Int. Ed. Engl. 2015; 127: 1607-1610Crossref 17Linder Grozhik A.V. Olarerin-George A.O. Meydan Single-nucleotide-resolution mapping m6Am throughout transcriptome.Nat. Methods. 12: 767-772Crossref (602) Since then, m6A-related vastly studied successively identified, subunits complex, demethylases, proteins, writers, erasers, readers, respectively (18Zheng Dahl Niu Fedorcsak Huang Li C.J. Vågbø C.B. Shi W.L. Song S.H. Z. Bosmans R.P.G. Hao Y.J. et al.ALKBH5 impacts fertility.Mol. Cell. 49: 18-29Abstract (1289) 19Wang B.X.S. Roundtree I.A. Ma H.H. Weng X.C. Chen H.L. modulates efficiency.Cell. 161: 1388-1399Abstract (1134) 20Shi Hsu P.J. YTHDF3 facilitates decay N6-methyladenosine-modified RNA.Cell 2017; 27: 315-328Crossref (514) 21Wang Gomez Hon G.C. Yue Parisien Ren N6-methyladenosine-dependent stability.Nature. 2014; 505: 117-120Crossref (1500) 22Schwartz Mumbach Jovanovic Maciag Bushkin G.G. Mertins Ter-Ovanesyan Habib Cacchiarelli Perturbation two distinct classes sites.Cell Rep. 8: 284-296Abstract (575) 23Horiuchi Kawamura Iwanari H. Ohashi Naito Kodama Hamakubo Wilms' tumor 1-associating alternative splicing cycle.J. 288: 33292-33302Abstract (177) 24Růžička Campilho Bodi Kashif Saleh Eeckhout El-Showk H.Y. Zhong S.L. Jaeger G.D. Mongan N.P. Hejátko Helariutta Fray R.G. factors required Arabidopsis conserved E3 ubiquitin ligase HAKAI.New Phytol. 215: 157-172Crossref (120) cotranscriptionally written METTL3-METTL14 core FTO ALKBH5 18Zheng 25Knuckles Carl Musheev Niehrs Wenger Bühler fate determination through cotranscriptional microprocessor binding.Nat. Struct. Mol. 24: 561-569Crossref (74) readers YTH domain family IGF2BP1-3 regulate processing, transcription, splicing, export, stability, (19Wang 26Zhang Theler Kaminska K.H. Hiller Stamm domain.J. 285: 14701-14710Abstract (140) 27Xu A.I. Tempel Min Structural basis selective YTHDC1 domain.Nat. 10: 927-929Crossref 28Alarcón C.R. Goodarzi Lee Tavazoie S.F. HNRNPA2B1 mediator m6A-dependent events.Cell. 162: 1299-1308Abstract (513) 29Liu structural switches RNA-protein interactions.Nature. 518: 560-564Crossref (793) 30Xiao Adhikari Dahal Y.S. Sun B.F. Ping X.L. Lai W.Y. al.Nuclear reader splicing.Mol. 2016; 61: 507-519Abstract (638) machineries has facilitated understanding processes (Fig. 1). development technology great importance studying m6A. Mass spectrometry identify changes overall content cells, high-throughput help us transcripts (31Wang Alvin Chew B.L. Dong Xu Balamkundu Cai W.M. Cui C.F. X.-Y. Quantifying epitranscriptome caps RNA.Nucleic 2019; 47e130Crossref (42) 32Yuan B.-F. Liquid chromatography-mass methylation.in: Methylation: Methods Protocols. Springer, New York, NY2017: 33-42Crossref poor specificity low resolution, hinders in-depth (33McIntyre A.B. Gokhale N.S. Cerchietti Horner S.M. Limits MeRIP/m6A-seq.Sci. 2020; 1-15Crossref To overcome shortcomings methods, used develop (34Zhang L.Q. Y.L. C.G. Z.J. Xie Single-base antibody-independent method.Sci. Adv. 5eaax0250Crossref (88) 35Garcia-Campos Edelheit Toth Safra Shachar Viukov Winkler Nir Lasman Brandis Deciphering "m6A code" quantitative profiling.Cell. 178: 731-747Abstract (115) 36Shu Cao Cheng M.H. Xiang S.Y. Gao M.S. Ying X.E. F.Q. Y.N. L.J. Y.Z. al.A metabolic labeling method detects transcriptome-wide single base resolution.Nat. 887-895Crossref 37Wang Xiao Yu Antibody-free enzyme-assisted approach N6-methyladenosine.Nat. 896-903Crossref (41) 38Xiao Tang Wei L.H. An elongation-and ligation-based qPCR amplification radiolabeling-free locus-specific modification.Angew. 57: 15995-16000Crossref Moreover, smoothly transitioned fundamental identification investigation pathological embryonic development, neurogenesis, various diseases 39Batista Molinie Qu Bouley D.M. Lujan Haddad Daneshvar controls transition stem cells.Cell Stem 707-719Abstract (562) 40Yoon K.-J. Ringeling F.R. Vissers Jacob Pokrass Jimenez-Cyrus Su Kim N.-S. Zhu Temporal control cortical neurogenesis methylation.Cell. 171: 877-889Abstract (274) basic mechanisms impact differential expression occurrence other initially investigated range, explaining certain (41Gokhale McIntyre McFadden M.J. Roder A.E. Kennedy E.M. Gandara Hopcraft S.E. Quicke Vazquez Willer Flaviviridae genomes infection.Cell Host Microbe. 20: 654-665Abstract (202) 42Lichinchi Wu Qin Rana T.M. Dynamics during Zika virus 666-673Abstract (182) 43Kim G.-W. Imam Khan Siddiqui hepatitis B C RNAs attenuates host innate immunity RIG-I signaling.J. 295: 13123-13133Abstract 44Zheng Q.L. Hou Zhou Z.Y. X.T. helicase DDX46 inhibits entrapping m6A-demethylated antiviral nucleus.Nat. Immunol. 18: 1094-1103Crossref (139) 45Wang Wen M.Y. Nuclear hnRNPA2B1 initiates amplifies immune response viruses.Science. 365eaav0758Crossref (79) 46Li Kang METTL3 enhances adhesion stabilizing integrin β1 m6A-HuR-dependent mechanism prostatic carcinoma.Am. Cancer 1012-1025PubMed 47Xia Miao promotes pancreatic proliferation invasion.Pathol. Pract. 152666Crossref (31) 48Li glioma influencing apoptosis.Cytogenet. Genome 159: 119-125Crossref (23) reliability completeness results still need improved with more precise past 2 years, combination CRISPR/Cas achieved editing, provides benign verifying regulating tools deeply (49Liu X.-M. Mao Ji Qian S.-B. Programmable CRISPR-Cas9 conjugates.Nat. 865-871Crossref (53) 50Ying Jiang H.Q. B.X. Y.P. X.W. Qi D.F. Yuan J.H. W.D. CDCP1 RCas9-methyltransferase like conjugates bladder development.Mol. Cancer. 19: 169Crossref (1) 51Wilson D.R. Cas13-directed methyltransferase.Nat. Biotechnol. 38: 1431-1440Crossref (40) 52Li J.X. G.Y. Ling Y.Y. Peng Y.x. Lin Chiang H.S. Targeted demethylation engineered dCas13b-ALKBH5 fusion protein.Nucleic 48: 5684-5694Crossref 53Liu Dou X.Y. C.Y. M.M. S.Q. Shen Y.W. chromosome-associated regulatory chromatin state transcription.Science. 367: 580-586Crossref (108) 54Mo Z.G. S.S. Ran R.X. Kong TRADES: SunTag system.Adv. 2001402Crossref (4) 55Zhao Jin Photoactivatable CRISPR-Cas13.Small. 1907301Crossref (16) focus erasers. will compare writers- erasers-assisted traditional plenty here elaborate recent findings especially progression. Finally, approaches developed conjugation system, could widely study. purified characterized 1990s catalytic subunit 1997 (56Bokar Shambaugh Polayes Matera Purification cDNA cloning AdoMet-binding (N6-adenosine)-methyltransferase.RNA. 1997; 1233-1247PubMed contains S-adenosyl methionine (SAM) DPPW motif (Asn-Pro-Pro-Trp) transferring SAM N6 position targeted 2, B). Later, METTL14 second component sharing around 43% sequence identity alignment (57Yue post-transcriptional gene regulation.Genes Dev. 1343-1355Crossref (394) 58Liu J.Z. Deng W.Z. METTL3–METTL14 mediates methylation.Nat. 93-95Crossref Biochemical studies show form heterodimer exhibit higher installation activity alone (58Liu crystal structure only bind SAM, structurally supports providing scaffold, substantially efficiency result (59Wang Feng Xue Guan Gong J.B. Zou T.T. Yin complex.Nature. 534: 575-578Crossref (357) 60Schöller Weichmann Treiber Ringle Flatley Feederle Bruckmann Meister Interactions, localization, phosphorylation generating METTL3–METTL14–WTAP complex.RNA. 499-512Crossref (119) 61Śledź Jinek insights writer complex.Elife. 5e18434Crossref Scholar) 2A). key pivotal (39Batista METTL3−/− mice early lethality (62Geula Mansour A.A. Kol Hershkovitz V. Peer Mor Manor Ben-Haim Eyal Yunger Pinto Jaitin D.A. al.m6A resolution naïve pluripotency toward differentiation.Science. 347: 1002-1006Crossref (737) depletion DmIME4 (METTL3 homolog) leads gametogenic defects Drosophila (63Hongay Orr-Weaver T.L. Inducer MEiosis 4 (IME4) Notch signaling oogenesis.Proc. 108: 14855-14860Crossref (123) Knockout brains both prolong cycle radial glia extend postnatal stages manner (40Yoon (WTAP) third classified factor 1 mammals (64Little N.A. Hastie N.D. Davies R.C. WTAP, tumour protein.Hum. 2000; 9: 2231-2239Crossref 65Small T.W. Pickering G.J. degradation Wilms survivin splice variant switching underlie IGF-1-mediated survival.J. 2009; 284: 24684-24695Abstract (18) While WTAP no catalytical targets, it assist locate speckles facilitate deposition (66Ping Lv Lou X.M. al.Mammalian methyltransferase.Cell 177-189Crossref (827) Virilizar found sex (67Hilfiker Nothiger temperature-sensitive mutation vir ts (virilizer) identifies Drosophila.Rouxs Arch. 1991; 200: 240-248Crossref (22) VIRMA, mammal homolog Virilizar, interact N-terminus (22Schwartz More recently, VIRMA verified associate polyadenylation preferentially mediating (68Yue Shu

Language: Английский

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RMDisease V2.0: an updated database of genetic variants that affect RNA modifications with disease and trait implication

Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 51(D1), P. D1388 - D1396

Published: Aug. 24, 2022

Recent advances in epitranscriptomics have unveiled functional associations between RNA modifications (RMs) and multiple human diseases, but distinguishing the or disease-related single nucleotide variants (SNVs) from majority of 'silent' remains a major challenge. We previously developed RMDisease database for unveiling association genetic RMs concerning disease pathogenesis. In this work, we present v2.0, an updated with expanded coverage. Using deep learning models 873 819 experimentally validated RM sites, identified total 1 366 252 RM-associated that may affect (add remove site) 16 different types (m6A, m5C, m1A, m5U, Ψ, m6Am, m7G, A-to-I, ac4C, Am, Cm, Um, Gm, hm5C, D f5C) 20 organisms (human, mouse, rat, zebrafish, maize, fruit fly, yeast, fission Arabidopsis, rice, chicken, goat, sheep, pig, cow, rhesus monkey, tomato, chimpanzee, green monkey SARS-CoV-2). Among them, 14 749 disease- 2441 trait-associated function via perturbation epitranscriptomic markers. v2.0 should serve as useful resource studying drivers phenotypes lie within epitranscriptome layer circuitry, is freely accessible at: www.rnamd.org/rmdisease2.

Language: Английский

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Emerging role of METTL3 in inflammatory diseases: mechanisms and therapeutic applications

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 21, 2023

Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney and autoimmune diseases have high incidence rates, still threaten human health, represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis various diseases. As most widely discussed m6A methyltransferase, pathogenic role METTL3 has become research hotspot, but there been no comprehensive review topic. Here, we summarize expression changes, modified target genes, related cardiovascular, metabolic, degenerative, immune, infectious well tumors. In addition epithelial cells, endothelial fibroblasts, also regulates function inflammation-related immune including macrophages, neutrophils, dendritic Th17 NK cells. Regarding therapeutic applications, serves for treatment with natural plant drug components, emodin, cinnamaldehyde, total flavonoids Abelmoschus manihot , resveratrol. This focuses on recent advances initiation, development, application Knowledge specific regulatory mechanisms involving can help deepen understanding lay foundation development precisely targeted drugs address processes.

Language: Английский

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Intracellular Fusobacterium nucleatum infection increases METTL3-mediated m6A methylation to promote the metastasis of esophageal squamous cell carcinoma

Journal of Advanced Research, Journal Year: 2023, Volume and Issue: 61, P. 165 - 178

Published: Aug. 22, 2023

The tumor-associated microbiota plays a vital role in cancer development. Accumulating evidence shows that Fusobacterium nucleatum (Fn) participates the progression of multiple tumor types. However, underlying mechanisms remain unclear. This study examined expression methyltransferase-like protein 3 (METTL3) during Fn infection and elucidated function pathway Fn-induced m6A methylation esophageal squamous cell carcinoma (ESCC). abundance patient tissues was determined by qPCR. Western blot, qRT-PCR, immunohistochemistry were performed to measure METTL3 cells tissues. evaluated vitro colony formation migration assays. MeRIP-qPCR determine relationship between c-Myc. In addition, half-lives genes are downstream with RNA stability enriched hepatocellular (HCC), breast (BRCA), ESCC, colorectal (CRC) positively associated ESCC could survive proliferation as well increase HCC, CRC, BRCA cells. Moreover, overexpression promoted proliferation, vivo vitro. Mechanistically, Intracellular increases transcription. c-Myc mRNA 3'-untranslated Region (3'-UTR) enhanced its YTH N6-Methyladenosine binding 1(YTHDF1)-dependent manner, which contributes induced metastasis. indicates intracellular promotes development metastasis, eradicating may be promising strategy for treating ESCC.

Language: Английский

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PCIF1-mediated deposition of 5′-cap N ⁶ ,2′- O -dimethyladenosine in ACE2 and TMPRSS2 mRNA regulates susceptibility to SARS-CoV-2 infection

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(5)

Published: Jan. 23, 2023

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a major health problem worldwide. Due the fast emergence of SARS-CoV-2 variants, understanding molecular mechanisms viral pathogenesis and developing novel inhibitors are essential urgent. Here, we investigated potential roles N 6 ,2′- O -dimethyladenosine (m A m ), one most abundant modifications eukaryotic messenger ribonucleic acid (mRNAs), in infection human cells. Using genome-wide -exo-seq, RNA sequencing analysis, Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing, demonstrate that phosphorylated C-terminal domain (CTD)-interacting factor 1 (PCIF1), cap-specific adenine -methyltransferase, plays role facilitating primary lung epithelial cells cell lines by SARS-CoV-2, variants concern, other coronaviruses. We show PCIF1 promotes sustaining expression receptors angiotensin-converting enzyme (ACE2) transmembrane serine protease (TMPRSS2) via -dependent mRNA stabilization. In PCIF1-depleted cells, both ACE2/TMPRSS2 rescued re-expression wild-type, but not catalytically inactive, PCIF1. These findings suggest for cap regulating susceptibility identify therapeutic target prevention infection.

Language: Английский

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