N6-Methyladenosine

N6-Methyladenosine
Names
IUPAC name
N-Methyladenosine
Other names
m6A
Identifiers
1867-73-8
ChemSpider 92307
Jmol 3D model Interactive image
PubChem 102175
Properties
C11H15N5O4
Molar mass 281.27 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

N6-Methyladenosine (m6A ) is an abundant modification in mRNA and is found within some viruses,[1][2] and most eukaryotes including mammals,[3][4][5][6] insects,[7] plants[8][9][10] and yeast.[11][12] It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist.[13][14]

Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit.[15] In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU[16] and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA[17] and in bovine prolactin mRNA.[18]

Species distribution

Yeast

In budding yeast (Sacharomyces cerevisiae), the homologue of METTL3, IME4 is induced in diploid cells in response to nitrogen and fermentable carbon source starvation and is required for mRNA methylation and the initiation of correct meiosis and sporulation.[11][12] mRNAs of IME1 and IME2, key early regulators of meiosis, are known to be targets for methylation, as are transcripts of IME4 itself.[12]

Plants

In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail.[19]

Mutations of MTA, the Arabidopsis thaliana homologue of METTL3, results in embryo arrest at the globular stage. A >90% reduction of m6A levels in mature plants leads to dramatically altered growth patterns and floral homeotic abnormalities.[19]

Mammals

Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of [G/A/U][G>A]m6AC[U>A/C][13][14] consistent with the previously identified motif. The localization of individual m6A sites in many mRNAs is highly similar between human and mouse,[13][14] and transcriptome-wide analysis reveals that m6A is found in regions of high evolutionary conservation.[13] m6A is found within long internal exons and is preferentially enriched within 3’ UTRs and around stop codons. m6A within 3’ UTRs is also associated with the presence of microRNA binding sites; roughly 2/3 of the mRNAs which contain an m6A site within their 3’ UTR also have at least one microRNA binding site.[13] Furthermore, precise m6A mapping by m6A-CLIP/IP (in multiple tissues/cultured cells of mouse and human) revealed that a majority of m6A locates in the last exon of mRNAs,[20] and the m6A enrichment around stop codons is a coincidence that many stop codons locate round the start of last exons where m6A is truly enriched.[20] The major presence of m6A in last exon (>=70%) allows the potential for 3'UTR regulation, including alternative polyadenylation.[20]

m6A is susceptible to dynamic regulation both throughout development and in response to cellular stimuli. Analysis of m6A in mouse brain RNA reveals that m6A levels are low during embryonic development and increase dramatically by adulthood.[13] Additionally, silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis.[14]

The importance of m6A methylation for physiological processes was recently demonstrated. Inhibition of m6A methylation via pharmacological inhibition of cellular methylations or more specifically by siRNA-mediated silencing of the m6A methylase Mettl3 led to the elongation of the circadian period. In contrast, overexpression of Mettl3 led to a shorter period. The mammalian circadian clock, composed of a transcription feedback loop tightly regulated to oscillate with a period of about 24 hours, is therefore extremely sensitive to perturbations in m6A-dependent RNA processing, likely due to the presence of m6A sites within clock gene transcripts.[21][22]

Clinical significance

The obesity risk gene, FTO, encodes the first identified m6A demethylase.[13][23] FTO mutations have been associated with increased risk for obesity and type 2 diabetes, which implicates m6A in important physiological pathways related to human disease. FTO knockdown with siRNA leads to increased amounts of m6A in poly(A) RNA,[14] whereas overexpression of FTO results in decreased amounts of m6A in human cells.[13] FTO partially localizes to nuclear speckles,[23] which supports the notion that m6A in nuclear RNA is a major physiological substrate of FTO. The consequences of FTO-guided demethylation are unknown, but it is likely to affect the processing of pre-mRNA, other nuclear RNAs, or both. The discovery that FTO functions as a cellular m6A demethylase suggests that increased FTO activity in patients with FTO mutations leads to abnormally low levels of m6A in target mRNAs, which through as-yet undefined pathways contributes to the onset of obesity and related diseases.

References

  1. ↑ Beemon K, Keith J (June 1977). "Localization of N6-methyladenosine in the Rous sarcoma virus genome". J. Mol. Biol. 113 (1): 165–79. doi:10.1016/0022-2836(77)90047-X. PMID 196091.
  2. ↑ Aloni Y, Dhar R, Khoury G (October 1979). "Methylation of nuclear simian virus 40 RNAs". J. Virol. 32 (1): 52–60. PMC 353526. PMID 232187.
  3. ↑ Desrosiers R, Friderici K, Rottman F (October 1974). "Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells". Proc. Natl. Acad. Sci. U.S.A. 71 (10): 3971–5. doi:10.1073/pnas.71.10.3971. PMC 434308. PMID 4372599.
  4. ↑ Adams JM, Cory S (May 1975). "Modified nucleosides and bizarre 5'-termini in mouse myeloma mRNA". Nature 255 (5503): 28–33. doi:10.1038/255028a0. PMID 1128665.
  5. ↑ Wei CM, Gershowitz A, Moss B (January 1976). "5'-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA". Biochemistry 15 (2): 397–401. doi:10.1021/bi00647a024. PMID 174715.
  6. ↑ Perry RP, Kelley DE, Friderici K, Rottman F (April 1975). "The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5' terminus". Cell 4 (4): 387–94. doi:10.1016/0092-8674(75)90159-2. PMID 1168101.
  7. ↑ Levis R, Penman S (April 1978). "5'-terminal structures of poly(A)+ cytoplasmic messenger RNA and of poly(A)+ and poly(A)- heterogeneous nuclear RNA of cells of the dipteran Drosophila melanogaster". J. Mol. Biol. 120 (4): 487–515. doi:10.1016/0022-2836(78)90350-9. PMID 418182.
  8. ↑ Nichols JL (1979). "In maize poly(A)-containing RNA". Plant Science Letters 15 (4): 357–361. doi:10.1016/0304-4211(79)90141-X.
  9. ↑ Kennedy TD, Lane BG (June 1979). "Wheat embryo ribonucleates. XIII. Methyl-substituted nucleoside constituents and 5'-terminal dinucleotide sequences in bulk poly(AR)-rich RNA from imbibing wheat embryos". Can. J. Biochem. 57 (6): 927–31. doi:10.1139/o79-112. PMID 476526.
  10. ↑ Zhong S, Li H, Bodi Z, Button J, Vespa L, Herzog M, Fray RG (May 2008). "MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor". Plant Cell 20 (5): 1278–88. doi:10.1105/tpc.108.058883. PMC 2438467. PMID 18505803.
  11. 1 2 Clancy MJ, Shambaugh ME, Timpte CS, Bokar JA (October 2002). "Induction of sporulation in Saccharomyces cerevisiae leads to the formation of N6-methyladenosine in mRNA: a potential mechanism for the activity of the IME4 gene". Nucleic Acids Res. 30 (20): 4509–18. doi:10.1093/nar/gkf573. PMC 137137. PMID 12384598.
  12. 1 2 3 Bodi Z, Button JD, Grierson D, Fray RG (September 2010). "Yeast targets for mRNA methylation". Nucleic Acids Res. 38 (16): 5327–35. doi:10.1093/nar/gkq266. PMC 2938207. PMID 20421205.
  13. 1 2 3 4 5 6 7 8 Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (May 2012). "Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3' UTRs and near Stop Codons". Cell 149 (7): 1635–46. doi:10.1016/j.cell.2012.05.003. PMC 3383396. PMID 22608085.
  14. 1 2 3 4 5 Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G (May 2012). "Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq". Nature 485 (7397): 201–6. doi:10.1038/nature11112. PMID 22575960.
  15. ↑ Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM (November 1997). "Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase". RNA 3 (11): 1233–47. PMC 1369564. PMID 9409616.
  16. ↑ Harper JE, Miceli SM, Roberts RJ, Manley JL (October 1990). "Sequence specificity of the human mRNA N6-adenosine methylase in vitro". Nucleic Acids Res. 18 (19): 5735–41. doi:10.1093/nar/18.19.5735. PMC 332308. PMID 2216767.
  17. ↑ Kane SE, Beemon K (September 1985). "Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: implications for RNA processing". Mol. Cell. Biol. 5 (9): 2298–306. PMC 366956. PMID 3016525.
  18. ↑ Horowitz S, Horowitz A, Nilsen TW, Munns TW, Rottman FM (September 1984). "Mapping of N6-methyladenosine residues in bovine prolactin mRNA". Proc. Natl. Acad. Sci. U.S.A. 81 (18): 5667–71. doi:10.1073/pnas.81.18.5667. PMC 391771. PMID 6592581.
  19. 1 2 Bodi Z, Zhong S, Mehra S, Song J, Graham N, Li H, May S, Fray RG (2012). "Adenosine Methylation in Arabidopsis mRNA is Associated with the 3' End and Reduced Levels Cause Developmental Defects". Front Plant Sci 3: 48. doi:10.3389/fpls.2012.00048. PMC 3355605. PMID 22639649.
  20. 1 2 3 Ke, S; Alemu, EA; Mertens, C; Gantman, EC; Fak, JJ; Mele, A; Haripal, B; Zucker-Scharff, I; Moore, MJ; Park, CY; Vågbø, CB; Kusnierczyk, A; Klungland, A; Darnell, JE; Darnell, RB (24 September 2015). "A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation.". Genes & Development 29 (19): 2037–53. doi:10.1101/gad.269415.115. PMID 26404942.
  21. ↑ Fustin JM, Doi M, Yamaguchi Y, Hayashi H, Nishimura S, Yoshida M, Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H (November 2013). "RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock". Cell 155 (4): 793–806. doi:10.1016/j.cell.2013.10.026. PMID 24209618.
  22. ↑ Hastings MH (November 2013). "m(6)A mRNA methylation: a new circadian pacesetter". Cell 155 (4): 740–1. doi:10.1016/j.cell.2013.10.028. PMID 24209613.
  23. 1 2 Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C (December 2011). "N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO". Nat. Chem. Biol. 7 (12): 885–7. doi:10.1038/nchembio.687. PMC 3218240. PMID 22002720.
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