N6-methyladenosine-dependent regulation of messenger RNA stability

Abstract

N6-methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA (mRNA) of all higher eukaryotes1,2. Although essential to cell viability and development3–5, the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease6–8. Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies9. The C-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA whereas the N-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selective-binding proteins to affect the translation status and lifetime of mRNA.

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

“…The change in the level of m6A modifiers in old PBMCs and senescent HDFs implies their involvement in mammalian aging and cellular senescence (Figures 4d and 5h). Dynamic regulation of m6A modification and mRNA decay is also dictated by position‐specific m6A methylation within the mRNA, and presence/activity of m6A‐binding proteins within a given context (Alarcón et al., 2015; Wang & He, 2014; Wang et al., 2014, 2015). A possibility is that DROSHA mRNA methylation is maintained by the presence of m6A readers or m6A‐regulated factors such as HuR, FMR1, and G3BP, resulting in preservation of DROSHA mRNA levels during the aging process (Edupuganti et al., 2017; Visvanathan et al., 2017).…”

“…Regulatory RNA modifications include A‐to‐I editing, pseudouridylation, methylation, and nicotinamide‐adenine dinucleotide (NAD + ) capping, which can regulate many cellular processes by influencing RNA metabolism (Jiao et al., 2017; Nishikura, 2016; Walters et al., 2016; Wang et al., 2014; Zhao, Roundtree & He, 2017). For example, A‐to‐I editing within a coding region of mRNA may lead to abnormal protein expressions that are not encoded in the genome, and editing within intronic regions could create new splice sites resulting in the inclusion of an undesired sequence in the mature mRNA (Nishikura, 2016).…”

Identification of factors required for m6A mRNA methylation in Arabidopsis reveals a role for the conserved E3 ubiquitin ligase HAKAI

“…N 6‐methyladenosine (m 6 A) is the most prevalent internal mRNA modification found in eukaryotes, and has received a burst of interest in recent years (Meyer & Jaffrey, 2014; Fray & Simpson, 2015; Yue et al ., 2015). m 6 A appears to be involved in a broad range of biological processes including mRNA export from the nucleus (Fustin et al ., 2013), regulation of splicing (Alarcón et al ., 2015b; Haussmann et al ., 2016; Lence et al ., 2016), mRNA translatability and stability (Wang et al ., 2014a,b, 2015; Bodi et al ., 2015; Zhou et al ., 2015), alternative polyadenylation site choice (Ke et al ., 2015) and other mechanisms accompanying RNA maturation (Meyer & Jaffrey, 2014; Yue et al ., 2015). m 6 A is essential for the earliest stages of pattern formation in plants (Zhong et al ., 2008; Bodi et al ., 2012; Shen et al ., 2016) and metazoans (Meyer & Jaffrey, 2014; Geula et al ., 2015; Yue et al ., 2015; Haussmann et al ., 2016; Lence et al ., 2016), linked with diseases in humans and other mammalian species (Jia et al ., 2011; Zheng et al ., 2013) and is required for meiosis in Saccharomyces cerevisiae (Clancy et al ., 2002).…”

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

“…A common epigenetic mark is 5‐methylcytosine,2 which has been termed the “fifth base” with potential functions on the control and regulation of gene transcription and protein translation by recruiting DNA‐binding proteins 2, 3. Similarly, a multitude of modifications, termed as epi‐transcriptomics, are identified on RNA from all three kingdoms of life 4. They are N6‐methyladenosine (m 6 A), N7‐methylguanosine, 5‐methylcytosine and N1‐methyladenosine, etc .…”