NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation

Qiu, Li; Li, Xiu; Tang, Hao; Jiang, Bin; Dou, Yali; Gorospe, Myriam; Wang, Wengong

doi:10.1002/jcb.25957

Cited by 191 publications

(155 citation statements)

References 35 publications

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“…These data also revealed a particularly high level of m 6 A (~51 m 6 A residues per gRNA) as well as high levels of 2’ O -methylated adenosine (Am), guanosine (Gm) and cytosine (Cm) (~27, ~25 and ~18 residues, respectively, per gRNA), as well as a high level of m 5 C (~13 residues per gRNA). These levels are considerably higher than previously reported for cellular poly(A)+ RNA (2, 21) (8). Specifically, the level of m 6 A reported for both human and murine poly(A)+ RNA is ~0.35% of “A” residues, while ~2.4% of all “A” residues in the MLV genome are m 6 A (Fig.…”

Section: Resultscontrasting

confidence: 70%

Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression

Courtney

Chalem

Bogerd

et al. 2019

Preprint

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12While it has been known for several years that viral RNAs are subject to the addition of 13 several distinct covalent modifications to individual nucleotides, collectively referred to as 14 epitranscriptomic modifications, the effect of these editing events on viral gene expression has 15 been controversial. Here, we report the purification of murine leukemia virus (MLV) genomic 16RNA to homogeneity and show that this viral RNA contains levels of N 6 -methyladenosine (m 6 A), 17 5-methylcytosine (m 5 C) and 2'O-methylated (Nm) ribonucleotides that are an order of 18 magnitude higher than detected on bulk cellular mRNAs. Mapping of m 6 A and m 5 C residues on 19 MLV transcripts identified multiple discrete editing sites and allowed the construction of MLV 20 variants bearing silent mutations that removed a subset of these sites. Analysis of the 21 replication potential of these mutants revealed a modest but significant attenuation in viral 22 replication in 3T3 cells in culture. Consistent with a positive role for m 6 A and m 5 C in viral 23 replication, we also demonstrate that overexpression of the key m 6 A reader protein YTHDF2 24 enhances MLV replication, while downregulation of the m 5 C writer NSUN2 inhibits MLV 25 replication. 26 Importance 27The data presented in this manuscript demonstrate that MLV RNAs bear an 28 exceptionally high level of the epitranscriptomic modifications m 6 A, m 5 C and Nm, thus 29 suggesting that these each facilitate some aspect of the viral replication cycle. Consistent with 30 this hypothesis, we demonstrate that mutational removal of a subset of these m 6 A or m 5 C 31 modifications from MLV transcripts inhibits MLV replication in cis and a similar result was also 32 observed upon manipulation of the level of expression of key cellular epitranscriptomic cofactors 33 in trans. Together, these results argue that the addition of several different epitranscriptomic 34 modifications to viral transcripts stimulates viral gene expression and suggest that MLV has 35 therefore evolved to maximize the level of these modifications that are added to viral RNAs. 36

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Section: Resultscontrasting

confidence: 70%

Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression

Courtney

Chalem

Bogerd

et al. 2019

Preprint

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“…These results indicated that RNA methyltransferase NSUN2 could affect p57 Kip2 mRNA stability. Wang et al found that different functional mechanisms of RNA methyltransferase NSUN2 depended on the location of methylation by m 5 C modification 19,20,[36][37][38] . Our dualluciferase reporter assay also found that the luciferase activity of the wild-type 3′-UTR of p57 Kip2 reporter gene was significantly enhanced, compared with the mutated 3′-UTR of p57 Kip2 reporter gene.…”

Section: Discussionmentioning

confidence: 99%

“…For m 5 C RIP, the standard procedure was described as previous study with some modifications 37,38 . Briefly, total RNAs were firstly isolated and treated with DNase.…”

Section: M5c Rna Rip Assaymentioning

confidence: 99%

RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57Kip2 by an m5C-dependent manner

et al. 2020

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The RNA methyltransferase NSUN2 has been involved in the cell proliferation and senescence, and is upregulated in various types of cancers. However, the role and potential mechanism of NSUN2 in gastric cancer remains to be determined. Our study showed that NSUN2 was significantly upregulated in gastric cancers, compared to adjacent normal gastric tissues. Moreover, NSUN2 could promote gastric cancer cell proliferation both in vitro and in vivo. Further study demonstrated that CDKN1C (p57 Kip2) was the potential downstream gene of regulated by NSUN2 in gastric cancer. NSUN2 could promote gastric cancer cell proliferation through repressing p57 Kip2 in an m 5 C-dependent manner. Our findings suggested that NSUN2 acted as an oncogene through promoting gastric cancer development by repressing p57 Kip2 in an m 5 C-dependent manner, which may provide a novel therapeutic target against gastric cancer.

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“…The latter was also observed in an in vitro translation system arguing against an indirect effect via NSUN2‐mediated tRNA methylation (see later section in this review). Conversely, methylation of specific cytosines in the 3′UTRs of the cell cycle regulators CDK1 and p21, respectively, was shown to promote translation of these mRNAs in vitro and in a reporter gene system in vivo (Li et al, ; Xing et al, ). Similarly, an m 5 C site within interleukin‐17A mRNA was observed to promote translation of IL‐17A (Wang, Tang, Wang, Wang, & Feng, ).…”

Section: ‐Methylcytosine In Abundant Rna Speciesmentioning

confidence: 99%

“…For instance, Nsun2 methylates specific vtRNAs, and this modification affects processing of a precursor vtRNA into svRNAs (Hussain, Sajini, et al, ). Last but not least, Nsun2 was described in several studies to target mRNAs (Hussain, Sajini, et al, ; Li, Li, et al, ; Squires et al, ; H. Tang et al, ; Xing et al, ). Recently, it was shown that only overexpression/suppression of NSUN2 but not of any other NSUN enzyme, affected overall m 5 C levels in mRNA from HeLa cells (Yang et al, ).…”

Section: ‐Methylcytosine In Abundant Rna Speciesmentioning

confidence: 99%

The dynamic RNA modification 5‐methylcytosine and its emerging role as an epitranscriptomic mark

2018

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It is a well‐known fact that RNA is the target of a plethora of modifications which currently amount to over a hundred. The vast majority of these modifications was observed in the two most abundant classes of RNA, rRNA and tRNA. With the recent advance in mapping technologies, modifications have been discovered also in mRNA and in less abundant non‐coding RNA species. These developments have sparked renewed interest in elucidating the nature and functions of those “epitransciptomic” modifications in RNA. N6‐methyladenosine (m6A) is the best understood and most frequent mark of mRNA with demonstrated functions ranging from pre‐mRNA processing, translation, miRNA biogenesis to mRNA decay. By contrast, much less research has been conducted on 5‐methylcytosine (m5C), which was detected in tRNAs and rRNAs and more recently in poly(A)RNAs. In this review, we discuss recent developments in the discovery of m5C RNA methylomes, the functions of m5C as well as the proteins installing, translating and manipulating this modification. Although our knowledge about m5C in RNA transcripts is just beginning to consolidate, it has become clear that cytosine methylation represents a powerful mechanistic strategy to regulate cellular processes on an epitranscriptomic level. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > tRNA Processing RNA Turnover and Surveillance > Regulation of RNA Stability

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NSUN2-Mediated m5C Methylation and METTL3/METTL14-Mediated m6A Methylation Cooperatively Enhance p21 Translation

Cited by 191 publications

References 35 publications

Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression

Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression

RNA methyltransferase NSUN2 promotes gastric cancer cell proliferation by repressing p57Kip2 by an m5C-dependent manner

The dynamic RNA modification 5‐methylcytosine and its emerging role as an epitranscriptomic mark

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