The m 6 A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells

Lin, Shuibin; Choe, Joong-Seon; Du, Peng; Triboulet, Robinson; Gregory, Richard I.

doi:10.1016/j.molcel.2016.03.021

Cited by 1,228 publications

(1,493 citation statements)

References 45 publications

(83 reference statements)

Supporting

Mentioning

1,364

Contrasting

Order By: Relevance

“…However, surprisingly, METTL3 promoted translation independent of its methyltransferase activity or m 6 A readers, because the catalytic domain of METTL3 showed no effect in promoting translation of the above oncogenes. In addition, knockdown of YTHDF1/YTHDF2 did not influence METTL3‐mediated translation 94. These findings provide us with insight into the mechanisms of m 6 A modification‐related proteins.…”

Section: The Dual Role Of M6a Modification In Human Cancersmentioning

confidence: 68%

See 1 more Smart Citation

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Wang

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

As the most abundant and reversible RNA modification in eukaryotic cells, m6A triggers a new layer of epi‐transcription. M6A modification occurs through a methylation process modified by “writers” complexes, reversed by “erasers”, and exerts its role depending on various “readers”. Emerging evidence shows that there is a strong association between m6A and human diseases, especially cancers. Herein, we review bi‐aspects of m6A in regulating cancers mediated by the m6A‐associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6A‐targeted therapies including competitive antagonists of m6A‐associated proteins may provide a new tumour intervention in the future.

show abstract

Section: The Dual Role Of M6a Modification In Human Cancersmentioning

confidence: 68%

“…Other studies find a new paradigm of how METTL3 affects tumour development independent of m 6 A modification 94. Lin et al.…”

Section: The Dual Role Of M6a Modification In Human Cancersmentioning

confidence: 99%

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Wang

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…Previous evidence showed that oocyte mRNA translation is controlled by two mechanisms: poly(A) tail length-correlated translation efficiency and 3Ј UTR element-mediated mRNA translation activation. Recently, evidence suggested a possible association of translation with RNA methylation (12,16,25), indicating that the 5Ј UTR m 6 A modification could initiate the translation of non-capped mRNAs. Through integrating the m 6 A-seq data and transcriptome/proteome data in X. laevis, we investigated m 6 A modification and possible roles of oocyte mRNAs.…”

Section: Discussionmentioning

confidence: 99%

N6-Methyladenosine Sequencing Highlights the Involvement of mRNA Methylation in Oocyte Meiotic Maturation and Embryo Development by Regulating Translation in Xenopus laevis

Wang

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

During the oogenesis of Xenopus laevis, oocytes accumulate maternal materials for early embryo development. As the transcription activity of the oocyte is silenced at the fully grown stage and the global genome is reactivated only by the mid-blastula embryo stage, the translation of maternal mRNAs accumulated during oocyte growth should be accurately regulated. Previous evidence has illustrated that the poly(A) tail length and RNA binding elements mediate RNA translation regulation in the oocyte. Recently, RNA methylation has been found to exist in various systems. In this study, we sequenced the N 6 -methyladenosine (m 6 A) modified mRNAs in fully grown germinal vesiclestage and metaphase II-stage oocytes. As a result, we identified 4207 mRNAs with m 6 A peaks in germinal vesicle-stage or metaphase II-stage oocytes. When we integrated the mRNA methylation data with transcriptome and proteome data, we found that the highly methylated mRNAs showed significantly lower protein levels than those of the hypomethylated mRNAs, although the RNA levels showed no significant difference. We also found that the hypomethylated mRNAs were mainly enriched in the cell cycle and translation pathways, whereas the highly methylated mRNAs were mainly associated with protein phosphorylation. Our results suggest that oocyte mRNA methylation can regulate cellular translation and cell division during oocyte meiotic maturation and early embryo development.During oogenesis in animals like Xenopus laevis, mouse, and human, germinal vesicle (GV)-stage 3 oocytes gradually achieve maximum size, and genomic transcription activity is silenced (1, 2). After that, the fully grown GV oocytes resume meiosis and develop to metaphase of the second meiosis (MII) stage. Then the oocyte is fertilized by sperm to form a zygote. The zygote starts mitosis, and embryo development is initiated. As embryo genomic transcription is not reactivated until embryo development to the mid-blastula stage for X. laevis (3) or the 2-cell to 16-cell stages for mammals (4 -7), oocytes or embryos need the maternal RNAs accumulated during oocyte growth to support new protein synthesis.As the synthesis of new proteins such as cyclins is of importance for the meiotic and mitotic events, the translation of maternal mRNAs during oocyte meiotic maturation and early embryo development should be precisely controlled. Previous data have shown that there are mainly two methods for cells to control the maternal mRNA translation in oocyte or early embryo protein binding to the cytoplasmic polyadenylation elements (CPEs) in maternal mRNAs and controlling the polyadenylation of the mRNA poly(A) tails (8). In most cases, shortened poly(A) tails of mRNAs repress their translation, whereas elongated poly(A) tails activate translation (9). The poly(A) tail length of oocyte mRNA is mainly associated with cytoplasmic polyadenylation, which is controlled by RNA binding proteins and associated proteins. The maternal mRNAs, whose 3Ј UTR contains a cis-element CPE, could be bonded by CPE binding...

show abstract

“…The prevalent internal RNA modification mark N(6)-methyladenosine (m 6 A) has been reported to play a role in regulating most facets of the RNA life cycle, including regulation of pre-mRNA splicing, mRNA stability, and mRNA translation (Lin et al, 2016;Liu et al, 2015;Wang et al, 2015Wang et al, , 2014Xiao et al, 2016;Zhao et al, 2014). Recently, work by us (Alarcón et al, 2015) and others (Ke et al, 2017;Knuckles et al, 2017) has established that m 6 A marks are deposited in the nucleus and are proposed to function in many nuclear regulatory processes, including microRNA and messenger RNA processing.…”

Section: Introductionmentioning

confidence: 99%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

View full text Add to dashboard Cite

SUMMARYPost-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m 6 A RNA methylation machinery to its target transcripts, where deposition of m 6 A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression. RESEARCH HIGHLIGHTS• The RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleus• Nuclear TARBP2 recruits the methyltransferase complex to deposit m 6 A marks on its target transcripts • TARBP2 and m 6 A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.• Increased TARBP2 expression is associated with lung cancer and promotes lung cancer growth in vivo.• The transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.

show abstract

The m 6 A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells

Cited by 1,228 publications

References 45 publications

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

N6-Methyladenosine Sequencing Highlights the Involvement of mRNA Methylation in Oocyte Meiotic Maturation and Embryo Development by Regulating Translation in Xenopus laevis

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Contact Info

Product

Resources

About