Naturally occurring modified ribonucleosides DOI Creative Commons
Phillip J. McCown, Agnieszka Ruszkowska, Charlotte N. Kunkler

et al.

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2020, Volume and Issue: 11(5)

Published: April 16, 2020

The chemical identity of RNA molecules beyond the four standard ribonucleosides has fascinated scientists since pseudouridine was characterized as "fifth" ribonucleotide in 1951. Since then, ever-increasing number and complexity modified have been found viruses throughout all three domains life. Such modifications can be simple methylations, hydroxylations, or thiolations, complex ring closures, glycosylations, acylations, aminoacylations, unusual incorporation selenium. While initially transfer ribosomal RNAs, also exist messenger RNAs noncoding RNAs. Modifications profound cellular outcomes at various levels, such altering structure being essential for cell survival organism viability. aberrant presence absence lead to human disease, ranging from cancer metabolic developmental illnesses Hoyeraal-Hreidarsson syndrome, Bowen-Conradi Williams-Beuren syndrome. In this review article, we summarize characterization 143 currently known by describing their taxonomic distributions, enzymes that generate modifications, any implications processes, structure, disease. We highlight areas active research, specific contain a particular type modification well methodologies used identify novel modifications. This article is categorized under: Processing > Editing Modification.

Language: Английский

Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers DOI Creative Commons
Hailing Shi, Jiangbo Wei, Chuan He

et al.

Molecular Cell, Journal Year: 2019, Volume and Issue: 74(4), P. 640 - 650

Published: May 1, 2019

Language: Английский

Citations

1474
The role of m6A modification in the biological functions and diseases DOI Creative Commons
Xiulin Jiang, Baiyang Liu, Zhi Nie

et al.

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

Citations

1400
Anti-tumour immunity controlled through mRNA m6A methylation and YTHDF1 in dendritic cells DOI
Dali Han, Jun Liu, Chuanyuan Chen

et al.

Nature, Journal Year: 2019, Volume and Issue: 566(7743), P. 270 - 274

Published: Feb. 1, 2019

Language: Английский

Citations

803
A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA DOI Creative Commons
Sara Zaccara, Samie R. Jaffrey

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

Citations

600
The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation DOI Creative Commons
Tao Liu,

Qinglv Wei,

Jing Jin

et al.

Nucleic Acids Research, Journal Year: 2020, Volume and Issue: 48(7), P. 3816 - 3831

Published: Jan. 22, 2020

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests key roles of m6A human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving protein translation thus affects overall production cancer cells largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified novel mechanism EIF3C, subunit initiation factor EIF3, as direct target YTHDF1. YTHDF1 augments EIF3C an m6A-dependent manner by binding to m6A-modified mRNA concomitantly promotes translational output, thereby facilitating tumorigenesis metastasis cancer. frequently amplified up-regulation associated with adverse prognosis patients. Furthermore, but not abundance increased positively correlates expression patients, suggesting more relevant role Collectively, identify YTHDF1-EIF3C axis critical progression which can serve develop therapeutics treatment.

Language: Английский

Citations

584
m 6 A RNA methylation: from mechanisms to therapeutic potential DOI Open Access
P. Cody He, Chuan He

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(3)

Published: Jan. 20, 2021

Language: Английский

Citations

504
Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation DOI Creative Commons
Huamin Wang, Xiang Hu,

Mingyan Huang

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: April 23, 2019

Abstract N6-methyladenosine (m 6 A) modification plays important roles in various cellular responses by regulating mRNA biology. However, how m A is involved innate immunity via affecting the translation of immune transcripts remains to be further investigated. Here we report that RNA methyltransferase Mettl3-mediated methylation promotes dendritic cell (DC) activation and function. Specific depletion Mettl3 DC resulted impaired phenotypic functional maturation DC, with decreased expression co-stimulatory molecules CD40, CD80 cytokine IL-12, reduced ability stimulate T both vitro vivo. Mechanistically, TLR4 signaling adaptor Tirap enhanced their for stimulating activation, strengthening TLR4/NF-κB signaling-induced production. Our findings identify a new role increasing certain physiological promotion DC-based response.

Language: Английский

Citations

410
The m6A methyltransferase METTL3 promotes bladder cancer progression via AFF4/NF-κB/MYC signaling network DOI Open Access
Maosheng Cheng, Sheng Lu, Qian Gao

et al.

Oncogene, Journal Year: 2019, Volume and Issue: 38(19), P. 3667 - 3680

Published: Jan. 18, 2019

Language: Английский

Citations

331
YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression DOI Creative Commons

Yulin Shi,

Songqing Fan,

Mengge Wu

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 25, 2019

Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved various human cancers evolved rapidly Tibetans six Tibetan domestic mammals compared to reciprocal lowlanders. Furthermore, m6A modified mRNA binding protein YTHDF1, one of evolutionary positively selected for high-altitude adaptation is amplified cancers, including non-small cell lung cancer (NSCLC). We show YTHDF1 deficiency inhibits NSCLC proliferation xenograft tumor formation through regulating the translational efficiency CDK2, CDK4, cyclin D1, depletion restrains de novo adenocarcinomas (ADC) progression. However, observe high expression correlates with better clinical outcome, its rendering cancerous cells resistant cisplatin (DDP) treatment. Mechanistic studies identified Keap1-Nrf2-AKR1C1 axis as downstream mediator YTHDF1. Together, these findings highlight critical role both hypoxia pathogenesis NSCLC.

Language: Английский

Citations

308
RNA methylomes reveal the m6A-mediated regulation of DNA demethylase gene SlDML2 in tomato fruit ripening DOI Creative Commons
Leilei Zhou, Shiping Tian, Guozheng Qin

et al.

Genome biology, Journal Year: 2019, Volume and Issue: 20(1)

Published: Aug. 6, 2019

Methylation of nucleotides, notably in the forms 5-methylcytosine (5mC) DNA and N6-methyladenosine (m6A) mRNA, carries important information for gene regulation. 5mC has been elucidated to participate regulation fruit ripening, whereas function m6A this process interplay between remain uncharacterized. Here, we show that mRNA methylation exhibits dynamic changes similar during tomato ripening. RNA methylome analysis reveals is a prevalent modification fruit, sites are enriched around stop codons within 3′ untranslated regions. In ripening-deficient epimutant Colorless non-ripening (Cnr) which harbors hypermethylation, over 1100 transcripts display increased levels, while only 134 decreased enrichment, suggesting global increase m6A. The deposition generally negatively correlated with transcript abundance. Further demonstrates overall Cnr mutant associated expression demethylase SlALKBH2, regulated by methylation. Interestingly, SlALKBH2 ability bind SlDML2, required modulates its stability via demethylation. Mutation decreases abundance SlDML2 delays Our study identifies novel layer key ripening genes establishes an essential molecular link

Language: Английский

Citations

280