Molecular Mechanisms Driving mRNA Degradation by m6A Modification

Yujin Lee, Junho Choe, Ok Hyun Park, Yoon Ki Kim

Research output: Contribution to journalReview articlepeer-review

202 Citations (Scopus)

Abstract

N6-Methyladenosine (m6A), 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 m6A-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 m6A reader protein)–CCR4/NOT (deadenylase) complex or endoribonucleolytic cleavage by the YTHDF2–HRSP12–ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some m6A-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 m6A and describe our current understanding of the dynamic regulation of m6A-mediated mRNA decay through the crosstalk between m6A (or YTHDF2) and other cellular factors.

Original languageEnglish
Pages (from-to)177-188
Number of pages12
JournalTrends in Genetics
Volume36
Issue number3
DOIs
Publication statusPublished - 2020 Mar

Bibliographical note

Funding Information:
The research in the laboratory of Y.K.K. and J.C. was supported by a National Research Foundation of Korea grant funded by the Korean Government (Ministry of Science, ICT and Future Planning; NRF-2015R1A3A2033665 and NRF-2018R1A5A1024261to Y.K.K. and NRF-2019R1F1A1062382 to J.C.). Y.L. was, in part, Fellowship Program through the National Research Foundation, South Korea.

Funding Information:
The research in the laboratory of Y.K.K. and J.C. was supported by a National Research Foundation of Korea grant funded by the Korean Government ( Ministry of Science, ICT and Future Planning ; NRF-2015R1A3A2033665 and NRF-2018R1A5A1024261 to Y.K.K. and NRF-2019R1F1A1062382 to J.C.). Y.L. was, in part, Fellowship Program through the National Research Foundation, South Korea. α-Ketoglutarate-dependent dioxygenase alk B homolog 5 (ALKBH5) mRNA demethylase that removes the methyl group from m 6 A. Adenylate- and uridylate-rich element (ARE)-mediated mRNA decay molecular mechanism eliciting rapid degradation of mRNAs containing AREs in their 3′UTR. The degradation efficiency is regulated by stabilizing factors (e.g., HuR) and destabilizing factors (e.g., TTP, BRF1/2). Endoribonuclease enzyme that cleaves the phosphodiester bond in a polynucleotide chain of either single-stranded or double-stranded RNA. Exoribonuclease enzyme that cleaves nucleotides at either the 5′ or the 3′ end of a polynucleotide chain. Exosome multiprotein complex with a 3′-to-5′ exoribonuclease activity that catalyzes the degradation of various types of RNA. Fat mass and obesity-associated protein (FTO) mRNA demethylase that removes the methyl group from m 6 A. Additionally, FTO demethylates m 6 A m at the first position after the 5′ cap. Fragile X mental retardation protein (FMRP) protein that is essential for cognitive development and related to fragile X syndrome and Parkinson’s disease. FMRP is also a recently identified context-dependent m 6 A reader that stabilizes m 6 A-containing mRNAs. Human antigen R (HuR) or ELAV-like protein 1 RBP that binds to U-rich regions and is known to stabilize its target mRNAs. m 6 A–METTL-associated complex (MACOM) complex comprising WTAP, RBM15, VIRMA, CBLL1, and ZC3H13. One or more of these factors interacts with the MAC to direct methylation at specific sites. m 6 A–METTL complex (MAC) m 6 A mRNA bound by the METTL3–14 heterodimer. Methyltransferase-like 3 (METTL3) catalytically active part of the methyltransferase complex. METTL3 is also known as MTA-70, MTA, or IME4. Methyltransferase-like 14 (METTL14) component of the m 6 A methyltransferase complex; appears to be catalytically inactive, but supports the methyltransferase activity of METTL3. miRNA small ncRNA ~22 nucleotides in length that functions in post-transcriptional gene silencing. A miRNA base pairs with complementary sequences in its target mRNA, leading to rapid degradation of the mRNA, its inefficient translation, or both. N 1 -Methyladenosine ( m 1 A) reversible modification found in tRNAs and mRNAs. The m 1 A modification of adenine at position 58 in tRNA is known to be crucial for tRNA stability. N 6 ,2′- O -Dimethyladenosine (m 6 A m ) reversible modification found at the +1 position from the 5′ cap in mRNA that affects mRNA fate. Neuronal RNA granules motile granules delivering translationally arrested mRNPs from the cell body to axons and dendrites. Nonsense-mediated mRNA decay the best-characterized mRNA surveillance mechanism, by which faulty mRNAs containing premature termination codons are selectively recognized and rapidly degraded. In addition, it functions as a post-transcriptional regulatory pathway by targeting normal physiological mRNAs, ensuring the proper cellular response to a variety of intrinsic and extrinsic cues. NSUN2 RNA methyltransferase that introduces m 5 C into tRNAs, mRNAs, miRNA, and ncRNAs. Processing bodies (P bodies) nonmembranous cytoplasmic foci where some transcripts are considered to be degraded and/or translationally repressed. Some transcripts can exit P bodies and resume translation. Stress granules dense cytosolic aggregates (comprising translationally arrested mRNPs) that appear when the cell is exposed to various stresses. YT521-B homology (YTH) domain-containing proteins family of reader proteins that specifically recognize m 6 A.

Publisher Copyright:
© 2019 The Authors

Keywords

  • HRSP12
  • RNase P/MRP
  • YTHDF2
  • circular RNA
  • endoribonucleolytic cleavage
  • mA modification

ASJC Scopus subject areas

  • Genetics

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