Molecular Mechanisms Driving mRNA Degradation by m6A Modification

Abstract

N 6 -Methyladenosine (m 6 A), the most prevalent internal modification associated with eukaryotic mRNAs, influences many steps of mRNA metabolism, including splicing, export, and translation, as well as stability. Recent studies have revealed that m 6 A-containing mRNAs undergo one of two distinct pathways of rapid degradation: deadenylation via the YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; an m 6 A reader protein)-CCR4/NOT (deadenylase) complex or endoribonucleolytic cleavage by the YTHDF2-HRSP12-ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some m 6 A-containing circular RNAs (circRNAs) are also subject to endoribonucleolytic cleavage by YTHDF2-HRSP12-RNase P/MRP. Here, we highlight recent progress on the molecular mechanisms underlying rapid mRNA degradation via m 6 A and describe our current understanding of the dynamic regulation of m 6 A-mediated mRNA decay through the crosstalk between m 6 A (or YTHDF2) and other cellular factors. RNA Modification: An Emerging Layer of Post-Transcriptional Gene RegulationMany recent studies point to the role of RNA modification as a mode of post-transcriptional gene regulation and this field has been termed 'epitranscriptomics' [1-4]. To date, approximately 150 post-transcriptional modifications have been associated with various RNA species, including mRNAs, tRNAs, rRNAs, noncoding RNAs (ncRNAs), and viral RNA genomes [5][6][7]. In this review, we summarize recent reports on m 6 A deposition and function. In particular, we discuss recent findings regarding how m 6 A contributes to mRNA stability at the molecular level. HighlightsN 6 -Methyladenosine (m 6 A) as an mRNA modification plays multiple roles in various steps/characteristics of mRNA processing and metabolism, such as splicing, export, translation, and stability.YTHDF2 preferentially recognizes m 6 A and recruits RNA-degrading enzymes or adaptor proteins to trigger rapid degradation of the m 6 A-containing mRNA.Depending on the presence of HRSP12binding sites in m 6 A-containing mRNAs, YTHDF2 elicits one of two RNA decay pathways: deadenylation by the YTHDF2-CCR4/NOT deadenylase complex or endoribonucleolytic cleavage via the YTHDF2-HRSP12-RNase P/MRP complex.The stability of m 6 A-containing mRNAs is regulated by the dynamic crosstalk between m 6 A and other cellular factors, such as RNA-binding proteins, RNA structures, and/or other types of modification.

METTL3-mediated m6A methylation negatively modulates autophagy to support blastocyst development

“…Thus, we identi ed a corresponding increase or decrease in the LC3 levels in METLL3 KD or OE embryos. Studies indicated that m6A modi cation has been strongly linked to increased mRNA degradation [37]. Our data further showed that m6A modi cation mostly happened at 3'UTR of ATG5 mRNA and m6A levels were increased or decreased upon METTL3 KD or OE.…”

The emerging role of RNA modifications in the regulation of mRNA stability

“…N 6 -methyladenosine m 6 A is the most abundant internal mRNA modification, and it affects various cellular and physiological processes, such as maternal-to-zygotic transition (MZT), cortical neurogenesis, and the regulation of cancer stem cells in acute myeloid leukemia 7,[14][15][16][17][18][19] . A transcriptome-wide analysis for identifying the consensus sequence motifs for the m 6 A modification in the human transcriptome revealed that m 6 A sites (Gm 6 AC or Am 6 AC) are found in noncoding RNAs and mRNAs, with a greater number within long exons and adjacent to stop codons 20,21 .…”

“…The m 6 A modification is cotranscriptionally generated in nascent transcripts by a methyltransferase complex comprising methyltransferase like 3 (METTL3), METTL14, WTAP, and KIAA1429 ( Fig. 1) 7,[17][18][19][22][23][24][25] . The methyltransferase complex transfers a methyl group to the N-6 position of the adenosine base.…”

“…The m 6 A modification plays a regulatory role in diverse molecular processes, such as transcription, pre-mRNA splicing, mRNA export, mRNA stability, and translation 7,[17][18][19] . The molecular events that occur through the m 6 A modification are guided by various m 6 A-recognizing reader proteins, such as YT521-B homology (YTH) domain-containing proteins.…”

“…YTHDF2 contains a P/Q/N-rich unstructured region in its N-terminal half, which is critical for YTHDF2 interactions with other cellular factors, and an RNA-binding domain in the Cterminal half, which is crucial for binding m 6 A-containing transcripts 25,[33][34][35] . When an m 6 A-containing mRNA is recognized by YTHDF2, rapid degradation of mRNA is initiated in one of two distinct pathways: the deadenylation pathway or the endoribonucleolytic pathway 19,33,36 . Rapid deadenylation of m 6 A-containing mRNA is accelerated by the recruitment of a deadenylase complex (CCR4-NOT complex) 37,38 to the m 6 Acontaining mRNA via a direct interaction with the Nterminus of YTHDF2 and the SH domain of CNOT1, a component of the CCR4-NOT complex 33 .…”