5′ UTR m6A Promotes Cap-Independent Translation

Meyer, Kate D.; Patil, Deepak P.; Zhou, Jun; Zinoviev, Alexandra; Skabkin, Maxim A.; Elemento, Olivier; Pestova, Tatyana V.; Qian, Shu‐Bing; Jaffrey, Samie R.

doi:10.1016/j.cell.2015.10.012

Cited by 1,505 publications

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“…Quantification of these modification events suggests they occur in many RNAs (2,3). Importantly, several of these modifications have functional consequences (4)(5)(6). For example, the presence of a single N 6 -methyladenosine within the 5′ UTR of an mRNA increases translation initiation (4).…”

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confidence: 99%

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Identification of NAD ⁺ capped mRNAs in Saccharomyces cerevisiae

Walters

Matheny

Mizoue

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

123

161

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RNAs besides tRNA and rRNA contain chemical modifications, including the recently described 5′ nicotinamide-adenine dinucleotide (NAD + ) RNA in bacteria. Whether 5′ NAD-RNA exists in eukaryotes remains unknown. We demonstrate that 5′ NAD-RNA is found on subsets of nuclear and mitochondrial encoded mRNAs in Saccharomyces cerevisiae. NAD-mRNA appears to be produced cotranscriptionally because NAD-RNA is also found on pre-mRNAs, and only on mitochondrial transcripts that are not 5′ end processed. These results define an additional 5′ RNA cap structure in eukaryotes and raise the possibility that this 5′ NAD + cap could modulate RNA stability and translation on specific subclasses of mRNAs.T he number and prevalence of known chemical modifications on mRNAs have dramatically increased in the past several years (1). Quantification of these modification events suggests they occur in many RNAs (2, 3). Importantly, several of these modifications have functional consequences (4-6). For example, the presence of a single N 6 -methyladenosine within the 5′ UTR of an mRNA increases translation initiation (4). In addition, the methylation status of cytosine residues within the 3′ UTR of the p16(INK4) human mRNA affects mRNA stability (6). Due to the increasing sensitivity of RNA sequencing (RNA-Seq) and small-molecule mass spectrometry, it is reasonable to hypothesize that many novel chemical modifications within mRNAs remain to be discovered.One modification recently identified in bacteria is 5′ nicotinamide-adenine dinucleotide (NAD + )-linked RNA (7, 8). Because canonical bacterial RNAs contain a 5′ triphosphate terminus, addition of NAD + to the 5′ end of RNAs represents a rudimentary "capping" mechanism, perhaps designed to impart specific properties for these RNAs by granting them a more structurally complex 5′ end. Consistent with this idea, NAD + addition to RNAs appears to occur during transcription initiation (9), as opposed to the more complex eukaryote 5′ capping, which occurs after transcription has commenced (10). Because the NAD + modification defines the 5′ end of NAD-RNAs, this modification can affect RNA stability in Escherichia coli (7, 9).For decades, 5′ end classification and study of eukaryotic mRNAs have been restricted to canonical 7-methylguanosine (m 7 G) "caps" and their methylated variants (11). The m 7 G cap modulates numerous facets of mRNA metabolism, including stability (12, 13), translation (14, 15), and export (16). The importance of this modification is underscored by the substantial cellular machinery dedicated to its addition and removal (17,18). Thus, mRNAs containing noncanonical 5′ termini may have distinct properties and be subject to alternative metabolic events.Described herein is the identification of NAD-RNAs in the eukaryote Saccharomyces cerevisiae. Examples of NAD-RNAs in S. cerevisiae include nuclear encoded mRNAs for ribosomal proteins, as well as some mitochondrial encoded transcripts. Our data suggest that the NAD + moiety is added during initiation in both nuclear and mitoc...

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confidence: 99%

“…Importantly, several of these modifications have functional consequences (4)(5)(6). For example, the presence of a single N 6 -methyladenosine within the 5′ UTR of an mRNA increases translation initiation (4). In addition, the methylation status of cytosine residues within the 3′ UTR of the p16(INK4) human mRNA affects mRNA stability (6).…”

mentioning

confidence: 99%

Identification of NAD ⁺ capped mRNAs in Saccharomyces cerevisiae

Walters

Matheny

Mizoue

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

123

161

View full text Add to dashboard Cite

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“…It has been shown that m 6 A modifications have different effects on mRNA translation when the m 6 A modifications occur at different regions of the mRNAs (14 -16). RNA methylation at the 5Ј UTR could promote mRNA translation, whereas RNA methylation at the last exons participated in the 3Ј UTR regulation of mRNAs (15,16 …”

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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

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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...

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“…78 It has also become clear that depending on the context of the modification and its localization, for instance in the 5 0 UTR or 3 0 UTR of a transcript, the same protein can coordinate with different cellular machinery and result in very different outcomes. 10,11 While substantial progress has been made in mapping RNA modification sites with high throughput sequencing-based approaches, some major challenges remain. First, in the majority of cases, even if single base resolution can be achieved, we cannot determine the absolute stoichiometry of modification at a given site.…”

Section: Discussionmentioning

confidence: 99%

Publisher's Note

2017

RNA Biology

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RNA modifications have long been known to be central in the proper function of tRNA and rRNA. While chemical modifications in mRNA were discovered decades ago, their function has remained largely mysterious until recently. Using enrichment strategies coupled to next generation sequencing, multiple modifications have now been mapped on a transcriptome-wide scale in a variety of contexts. We now know that RNA modifications influence cell biology by many different mechanisms -by influencing RNA structure, by tuning interactions within the ribosome, and by recruiting specific binding proteins that intersect with other signaling pathways. They are also dynamic, changing in distribution or level in response to stresses such as heat shock and nutrient deprivation. Here, we provide an overview of recent themes that have emerged from the substantial progress that has been made in our understanding of chemical modifications across many major RNA classes in eukaryotes.

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5′ UTR m6A Promotes Cap-Independent Translation

Cited by 1,505 publications

References 32 publications

Identification of NAD ⁺ capped mRNAs in Saccharomyces cerevisiae

Identification of NAD ⁺ capped mRNAs in Saccharomyces cerevisiae

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

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5′ UTR m6A Promotes Cap-Independent Translation

Cited by 1,505 publications

References 32 publications

Identification of NAD + capped mRNAs in Saccharomyces cerevisiae

Identification of NAD + capped mRNAs in Saccharomyces cerevisiae

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

Publisher's Note

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Identification of NAD ⁺ capped mRNAs in Saccharomyces cerevisiae

Identification of NAD ⁺ capped mRNAs in Saccharomyces cerevisiae