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'''''N''<sup>6</sup>-Methyladenosine''' (m<sup>6</sup>A ) is an abundant modification in [[mRNA]] and is found within some viruses,<ref name="pmid196091">{{cite journal | vauthors = Beemon K, Keith J | title = Localization of N6-methyladenosine in the Rous sarcoma virus genome | journal = Journal of Molecular Biology | volume = 113 | issue = 1 | pages = 165–79 | date = June 1977 | pmid = 196091 | doi = 10.1016/0022-2836(77)90047-X }}</ref><ref name="pmid232187">{{cite journal | vauthors = Aloni Y, Dhar R, Khoury G | title = Methylation of nuclear simian virus 40 RNAs | journal = Journal of Virology | volume = 32 | issue = 1 | pages = 52–60 | date = October 1979 | pmid = 232187 | pmc = 353526 | doi = }}</ref> and most eukaryotes including mammals,<ref name="pmid4372599">{{cite journal | vauthors = Desrosiers R, Friderici K, Rottman F | title = Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 10 | pages = 3971–5 | date = October 1974 | pmid = 4372599 | pmc = 434308 | doi = 10.1073/pnas.71.10.3971 }}</ref><ref name="pmid1128665">{{cite journal | vauthors = Adams JM, Cory S | title = Modified nucleosides and bizarre 5'-termini in mouse myeloma mRNA | journal = Nature | volume = 255 | issue = 5503 | pages = 28–33 | date = May 1975 | pmid = 1128665 | doi = 10.1038/255028a0 }}</ref><ref name="pmid174715">{{cite journal | vauthors = Wei CM, Gershowitz A, Moss B | title = 5'-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA | journal = Biochemistry | volume = 15 | issue = 2 | pages = 397–401 | date = January 1976 | pmid = 174715 | doi = 10.1021/bi00647a024 }}</ref><ref name="pmid1168101">{{cite journal | vauthors = Perry RP, Kelley DE, Friderici K, Rottman F | title = The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5' terminus | journal = Cell | volume = 4 | issue = 4 | pages = 387–94 | date = April 1975 | pmid = 1168101 | doi = 10.1016/0092-8674(75)90159-2 }}</ref> insects,<ref name="pmid418182">{{cite journal | vauthors = Levis R, Penman S | title = 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 | journal = Journal of Molecular Biology | volume = 120 | issue = 4 | pages = 487–515 | date = April 1978 | pmid = 418182 | doi = 10.1016/0022-2836(78)90350-9 }}</ref> plants<ref name=Nich1>{{cite journal | vauthors =Nichols JL | title = In maize poly(A)-containing RNA | year = 1979 | journal = Plant Science Letters | volume = 15 | issue = 4 | pages = 357–361 | doi = 10.1016/0304-4211(79)90141-X }}</ref><ref name="pmid476526">{{cite journal | vauthors = Kennedy TD, Lane BG | title = Wheat embryo ribonucleates. XIII. Methyl-substituted nucleoside constituents and 5'-terminal dinucleotide sequences in bulk poly(AR)-rich RNA from imbibing wheat embryos | journal = Canadian Journal of Biochemistry | volume = 57 | issue = 6 | pages = 927–31 | date = June 1979 | pmid = 476526 | doi = 10.1139/o79-112 }}</ref><ref name="pmid18505803">{{cite journal | vauthors = Zhong S, Li H, Bodi Z, Button J, Vespa L, Herzog M, Fray RG | title = MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor | journal = The Plant Cell | volume = 20 | issue = 5 | pages = 1278–88 | date = May 2008 | pmid = 18505803 | pmc = 2438467 | doi = 10.1105/tpc.108.058883 }}</ref> and yeast.<ref name="Clancy_2002">{{cite journal | vauthors = Clancy MJ, Shambaugh ME, Timpte CS, Bokar JA | title = 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 | journal = Nucleic Acids Research | volume = 30 | issue = 20 | pages = 4509–18 | date = October 2002 | pmid = 12384598 | pmc = 137137 | doi = 10.1093/nar/gkf573 }}</ref><ref name="Bodi_2010">{{cite journal | vauthors = Bodi Z, Button JD, Grierson D, Fray RG | title = Yeast targets for mRNA methylation | journal = Nucleic Acids Research | volume = 38 | issue = 16 | pages = 5327–35 | date = September 2010 | pmid = 20421205 | pmc = 2938207 | doi = 10.1093/nar/gkq266 }}</ref> It is also found in [[tRNA]], [[rRNA]], and [[small nuclear RNA]] (snRNA) as well as several [[long non-coding RNA]], such as ''[[Xist]]''.<ref name="Meyer_2012">{{cite journal | vauthors = Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR | title = Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons | journal = Cell | volume = 149 | issue = 7 | pages = 1635–46 | date = June 2012 | pmid = 22608085 | pmc = 3383396 | doi = 10.1016/j.cell.2012.05.003 }}</ref><ref name="Dominissini_2012">{{cite journal | vauthors = 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 | title = Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq | journal = Nature | volume = 485 | issue = 7397 | pages = 201–6 | date = April 2012 | pmid = 22575960 | doi = 10.1038/nature11112 }}</ref>
'''''N''<sup>6</sup>-Methyladenosine''' (m<sup>6</sup>A) is an abundant modification in [[mRNA]] and is found within some viruses,<ref name="pmid196091">{{cite journal | vauthors = Beemon K, Keith J | title = Localization of N6-methyladenosine in the Rous sarcoma virus genome | journal = Journal of Molecular Biology | volume = 113 | issue = 1 | pages = 165–79 | date = June 1977 | pmid = 196091 | doi = 10.1016/0022-2836(77)90047-X }}</ref><ref name="pmid232187">{{cite journal | vauthors = Aloni Y, Dhar R, Khoury G | title = Methylation of nuclear simian virus 40 RNAs | journal = Journal of Virology | volume = 32 | issue = 1 | pages = 52–60 | date = October 1979 | pmid = 232187 | pmc = 353526 | doi = }}</ref> and most eukaryotes including mammals,<ref name="pmid4372599">{{cite journal | vauthors = Desrosiers R, Friderici K, Rottman F | title = Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 10 | pages = 3971–5 | date = October 1974 | pmid = 4372599 | pmc = 434308 | doi = 10.1073/pnas.71.10.3971 }}</ref><ref name="pmid1128665">{{cite journal | vauthors = Adams JM, Cory S | title = Modified nucleosides and bizarre 5'-termini in mouse myeloma mRNA | journal = Nature | volume = 255 | issue = 5503 | pages = 28–33 | date = May 1975 | pmid = 1128665 | doi = 10.1038/255028a0 }}</ref><ref name="pmid174715">{{cite journal | vauthors = Wei CM, Gershowitz A, Moss B | title = 5'-Terminal and internal methylated nucleotide sequences in HeLa cell mRNA | journal = Biochemistry | volume = 15 | issue = 2 | pages = 397–401 | date = January 1976 | pmid = 174715 | doi = 10.1021/bi00647a024 }}</ref><ref name="pmid1168101">{{cite journal | vauthors = Perry RP, Kelley DE, Friderici K, Rottman F | title = The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5' terminus | journal = Cell | volume = 4 | issue = 4 | pages = 387–94 | date = April 1975 | pmid = 1168101 | doi = 10.1016/0092-8674(75)90159-2 }}</ref> insects,<ref name="pmid418182">{{cite journal | vauthors = Levis R, Penman S | title = 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 | journal = Journal of Molecular Biology | volume = 120 | issue = 4 | pages = 487–515 | date = April 1978 | pmid = 418182 | doi = 10.1016/0022-2836(78)90350-9 }}</ref> plants<ref name=Nich1>{{cite journal | vauthors =Nichols JL | title = In maize poly(A)-containing RNA | year = 1979 | journal = Plant Science Letters | volume = 15 | issue = 4 | pages = 357–361 | doi = 10.1016/0304-4211(79)90141-X }}</ref><ref name="pmid476526">{{cite journal | vauthors = Kennedy TD, Lane BG | title = Wheat embryo ribonucleates. XIII. Methyl-substituted nucleoside constituents and 5'-terminal dinucleotide sequences in bulk poly(AR)-rich RNA from imbibing wheat embryos | journal = Canadian Journal of Biochemistry | volume = 57 | issue = 6 | pages = 927–31 | date = June 1979 | pmid = 476526 | doi = 10.1139/o79-112 }}</ref><ref name="pmid18505803">{{cite journal | vauthors = Zhong S, Li H, Bodi Z, Button J, Vespa L, Herzog M, Fray RG | title = MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor | journal = The Plant Cell | volume = 20 | issue = 5 | pages = 1278–88 | date = May 2008 | pmid = 18505803 | pmc = 2438467 | doi = 10.1105/tpc.108.058883 }}</ref> and yeast.<ref name="Clancy_2002">{{cite journal | vauthors = Clancy MJ, Shambaugh ME, Timpte CS, Bokar JA | title = 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 | journal = Nucleic Acids Research | volume = 30 | issue = 20 | pages = 4509–18 | date = October 2002 | pmid = 12384598 | pmc = 137137 | doi = 10.1093/nar/gkf573 }}</ref><ref name="Bodi_2010">{{cite journal | vauthors = Bodi Z, Button JD, Grierson D, Fray RG | title = Yeast targets for mRNA methylation | journal = Nucleic Acids Research | volume = 38 | issue = 16 | pages = 5327–35 | date = September 2010 | pmid = 20421205 | pmc = 2938207 | doi = 10.1093/nar/gkq266 }}</ref> It is also found in [[tRNA]], [[rRNA]], and [[small nuclear RNA]] (snRNA) as well as several [[long non-coding RNA]], such as ''[[Xist]]''.<ref name="Meyer_2012">{{cite journal | vauthors = Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR | title = Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons | journal = Cell | volume = 149 | issue = 7 | pages = 1635–46 | date = June 2012 | pmid = 22608085 | pmc = 3383396 | doi = 10.1016/j.cell.2012.05.003 }}</ref><ref name="Dominissini_2012">{{cite journal | vauthors = 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 | title = Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq | journal = Nature | volume = 485 | issue = 7397 | pages = 201–6 | date = April 2012 | pmid = 22575960 | doi = 10.1038/nature11112 }}</ref>


[[Adenosine]] [[methylation]] is directed by a large m<sup>6</sup>A [[methyltransferase]] complex containing [[METTL3]] as the SAM-binding sub-unit.<ref name="pmid9409616">{{cite journal | vauthors = Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM | title = Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase | journal = RNA | volume = 3 | issue = 11 | pages = 1233–47 | date = November 1997 | pmid = 9409616 | pmc = 1369564 | doi = }}</ref> ''In vitro'', this methyltransferase complex preferentially methylates RNA [[oligonucleotides]] containing GGACU<ref name="pmid2216767">{{cite journal | vauthors = Harper JE, Miceli SM, Roberts RJ, Manley JL | title = Sequence specificity of the human mRNA N6-adenosine methylase in vitro | journal = Nucleic Acids Research | volume = 18 | issue = 19 | pages = 5735–41 | date = October 1990 | pmid = 2216767 | pmc = 332308 | doi = 10.1093/nar/18.19.5735 }}</ref> and a similar preference was identified ''in vivo'' in mapped m<sup>6</sup>A sites in Rous sarcoma virus genomic RNA<ref name="pmid3016525">{{cite journal | vauthors = Kane SE, Beemon K | title = Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: implications for RNA processing | journal = Molecular and Cellular Biology | volume = 5 | issue = 9 | pages = 2298–306 | date = September 1985 | pmid = 3016525 | pmc = 366956 | doi = 10.1128/mcb.5.9.2298 }}</ref> and in bovine prolactin mRNA.<ref name="pmid6592581">{{cite journal | vauthors = Horowitz S, Horowitz A, Nilsen TW, Munns TW, Rottman FM | title = Mapping of N6-methyladenosine residues in bovine prolactin mRNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 18 | pages = 5667–71 | date = September 1984 | pmid = 6592581 | pmc = 391771 | doi = 10.1073/pnas.81.18.5667 }}</ref>
[[Adenosine]] [[methylation]] is directed by a large m<sup>6</sup>A [[methyltransferase]] complex containing [[METTL3]] as the SAM-binding sub-unit.<ref name="pmid9409616">{{cite journal | vauthors = Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM | title = Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase | journal = RNA | volume = 3 | issue = 11 | pages = 1233–47 | date = November 1997 | pmid = 9409616 | pmc = 1369564 | doi = }}</ref> ''In vitro'', this methyltransferase complex preferentially methylates RNA [[oligonucleotides]] containing GGACU<ref name="pmid2216767">{{cite journal | vauthors = Harper JE, Miceli SM, Roberts RJ, Manley JL | title = Sequence specificity of the human mRNA N6-adenosine methylase in vitro | journal = Nucleic Acids Research | volume = 18 | issue = 19 | pages = 5735–41 | date = October 1990 | pmid = 2216767 | pmc = 332308 | doi = 10.1093/nar/18.19.5735 }}</ref> and a similar preference was identified ''in vivo'' in mapped m<sup>6</sup>A sites in Rous sarcoma virus genomic RNA<ref name="pmid3016525">{{cite journal | vauthors = Kane SE, Beemon K | title = Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: implications for RNA processing | journal = Molecular and Cellular Biology | volume = 5 | issue = 9 | pages = 2298–306 | date = September 1985 | pmid = 3016525 | pmc = 366956 | doi = 10.1128/mcb.5.9.2298 }}</ref> and in bovine prolactin mRNA.<ref name="pmid6592581">{{cite journal | vauthors = Horowitz S, Horowitz A, Nilsen TW, Munns TW, Rottman FM | title = Mapping of N6-methyladenosine residues in bovine prolactin mRNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 81 | issue = 18 | pages = 5667–71 | date = September 1984 | pmid = 6592581 | pmc = 391771 | doi = 10.1073/pnas.81.18.5667 }}</ref> More recent studies have characterized other key components of the m<sup>6</sup>A methyltransferase complex in mammals, including METTL14<ref name=":0">{{Cite journal|last=Liu|first=Jianzhao|last2=Yue|first2=Yanan|last3=Han|first3=Dali|last4=Wang|first4=Xiao|last5=Fu|first5=Ye|last6=Zhang|first6=Liang|last7=Jia|first7=Guifang|last8=Yu|first8=Miao|last9=Lu|first9=Zhike|title=A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation|url=http://www.nature.com/doifinder/10.1038/nchembio.1432|journal=Nature Chemical Biology|volume=10|issue=2|pages=93–95|doi=10.1038/nchembio.1432|pmc=3911877|pmid=24316715}}</ref><ref>{{Cite journal|last=Wang|first=Yang|last2=Li|first2=Yue|last3=Toth|first3=Julia I.|last4=Petroski|first4=Matthew D.|last5=Zhang|first5=Zhaolei|last6=Zhao|first6=Jing Crystal|title=N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells|url=http://www.nature.com/doifinder/10.1038/ncb2902|journal=Nature Cell Biology|volume=16|issue=2|pages=191–198|doi=10.1038/ncb2902|pmc=4640932|pmid=24394384}}</ref>, Wilms tumor 1 associated protein (WTAP)<ref name=":0" /><ref>{{Cite journal|last=Ping|first=Xiao-Li|last2=Sun|first2=Bao-Fa|last3=Wang|first3=Lu|last4=Xiao|first4=Wen|last5=Yang|first5=Xin|last6=Wang|first6=Wen-Jia|last7=Adhikari|first7=Samir|last8=Shi|first8=Yue|last9=Lv|first9=Ying|date=2014-02-01|title=Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase|url=http://www.nature.com/cr/journal/v24/n2/full/cr20143a.html|journal=Cell Research|language=en|volume=24|issue=2|pages=177–189|doi=10.1038/cr.2014.3|issn=1001-0602|pmc=3915904|pmid=24407421}}</ref> and KIAA1429<ref>{{Cite journal|last=Schwartz|first=Schraga|last2=Mumbach|first2=Maxwell R.|last3=Jovanovic|first3=Marko|last4=Wang|first4=Tim|last5=Maciag|first5=Karolina|last6=Bushkin|first6=G. Guy|last7=Mertins|first7=Philipp|last8=Ter-Ovanesyan|first8=Dmitry|last9=Habib|first9=Naomi|title=Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites|url=http://linkinghub.elsevier.com/retrieve/pii/S2211124714004422|journal=Cell Reports|volume=8|issue=1|pages=284–296|doi=10.1016/j.celrep.2014.05.048|pmc=4142486|pmid=24981863}}</ref>. Following a 2010 speculation of m<sup>6</sup>A in mRNA being dynamic and reversible<ref>{{Cite journal|last=He|first=Chuan|date=2010-12-01|title=Grand challenge commentary: RNA epigenetics?|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=21079590&amp;dopt=Abstract|journal=Nature Chemical Biology|volume=6|issue=12|pages=863–865|doi=10.1038/nchembio.482|issn=1552-4469|pmid=21079590}}</ref>, the discovery of the first m<sup>6</sup>A demethylase, fat mass and obesity-associated protein (FTO) in 2011<ref>{{Cite journal|last=Jia|first=Guifang|last2=Fu|first2=Ye|last3=Zhao|first3=Xu|last4=Dai|first4=Qing|last5=Zheng|first5=Guanqun|last6=Yang|first6=Ying|last7=Yi|first7=Chengqi|last8=Lindahl|first8=Tomas|last9=Pan|first9=Tao|date=2011-10-16|title=N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=22002720&amp;dopt=Abstract|journal=Nature Chemical Biology|volume=7|issue=12|pages=885–887|doi=10.1038/nchembio.687|issn=1552-4469|pmc=3218240|pmid=22002720}}</ref> confirmed this hypothesis and revitalized the interests in the study of m<sup>6</sup>A. A second m<sup>6</sup>A demethylase alkB homolog 5 (ALKBH5) was later discovered as well<ref>{{Cite journal|last=Zheng|first=Guanqun|last2=Dahl|first2=John Arne|last3=Niu|first3=Yamei|last4=Fedorcsak|first4=Peter|last5=Huang|first5=Chun-Min|last6=Li|first6=Charles J.|last7=Vågbø|first7=Cathrine B.|last8=Shi|first8=Yue|last9=Wang|first9=Wen-Ling|date=2013-01-10|title=ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=23177736&amp;dopt=Abstract|journal=Molecular Cell|volume=49|issue=1|pages=18–29|doi=10.1016/j.molcel.2012.10.015|issn=1097-4164|pmc=3646334|pmid=23177736}}</ref>.

The biological functions of m<sup>6</sup>A are mediated through a group of RNA binding proteins that specifically recognize the methylated adenosine on RNA. These binding proteins are named m<sup>6</sup>A readers. The YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3 and YTHDC1) have been characterized as direct m<sup>6</sup>A readers and have a conserved m<sup>6</sup>A-binding pocket<ref name="Dominissini_2012" /><ref>{{Cite journal|last=Wang|first=Xiao|last2=Lu|first2=Zhike|last3=Gomez|first3=Adrian|last4=Hon|first4=Gary C.|last5=Yue|first5=Yanan|last6=Han|first6=Dali|last7=Fu|first7=Ye|last8=Parisien|first8=Marc|last9=Dai|first9=Qing|date=2014-01-02|title=N6-methyladenosine-dependent regulation of messenger RNA stability|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=24284625&amp;dopt=Abstract|journal=Nature|volume=505|issue=7481|pages=117–120|doi=10.1038/nature12730|issn=1476-4687|pmc=3877715|pmid=24284625}}</ref><ref>{{Cite journal|last=Wang|first=Xiao|last2=Zhao|first2=Boxuan Simen|last3=Roundtree|first3=Ian A.|last4=Lu|first4=Zhike|last5=Han|first5=Dali|last6=Ma|first6=Honghui|last7=Weng|first7=Xiaocheng|last8=Chen|first8=Kai|last9=Shi|first9=Hailing|date=2015-06-04|title=N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=26046440&amp;dopt=Abstract|journal=Cell|volume=161|issue=6|pages=1388–1399|doi=10.1016/j.cell.2015.05.014|issn=1097-4172|pmc=4825696|pmid=26046440}}</ref><ref>{{Cite journal|last=Xu|first=Chao|last2=Wang|first2=Xiao|last3=Liu|first3=Ke|last4=Roundtree|first4=Ian A.|last5=Tempel|first5=Wolfram|last6=Li|first6=Yanjun|last7=Lu|first7=Zhike|last8=He|first8=Chuan|last9=Min|first9=Jinrong|date=2014-11-01|title=Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=25242552&amp;dopt=Abstract|journal=Nature Chemical Biology|volume=10|issue=11|pages=927–929|doi=10.1038/nchembio.1654|issn=1552-4469|pmid=25242552}}</ref><ref>{{Cite journal|last=Xiao|first=Wen|last2=Adhikari|first2=Samir|last3=Dahal|first3=Ujwal|last4=Chen|first4=Yu-Sheng|last5=Hao|first5=Ya-Juan|last6=Sun|first6=Bao-Fa|last7=Sun|first7=Hui-Ying|last8=Li|first8=Ang|last9=Ping|first9=Xiao-Li|date=2016-02-18|title=Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=26876937&amp;dopt=Abstract|journal=Molecular Cell|volume=61|issue=4|pages=507–519|doi=10.1016/j.molcel.2016.01.012|issn=1097-4164|pmid=26876937}}</ref><ref>{{Cite journal|last=Luo|first=Shukun|last2=Tong|first2=Liang|date=2014-09-23|title=Molecular basis for the recognition of methylated adenines in RNA by the eukaryotic YTH domain|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=25201973&amp;dopt=Abstract|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=111|issue=38|pages=13834–13839|doi=10.1073/pnas.1412742111|issn=1091-6490|pmc=4183320|pmid=25201973}}</ref><ref>{{Cite journal|last=Zhu|first=Tingting|last2=Roundtree|first2=Ian A.|last3=Wang|first3=Ping|last4=Wang|first4=Xiao|last5=Wang|first5=Li|last6=Sun|first6=Chang|last7=Tian|first7=Yuan|last8=Li|first8=Jie|last9=He|first9=Chuan|date=2014-12-01|title=Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=25412661&amp;dopt=Abstract|journal=Cell Research|volume=24|issue=12|pages=1493–1496|doi=10.1038/cr.2014.152|issn=1748-7838|pmc=4260350|pmid=25412661}}</ref>. These m<sup>6</sup>A readers, together with m<sup>6</sup>A methyltransferases (writers) and demethylases (erasers), establish a complex mechanism of m<sup>6</sup>A regulation in which writers and erasers determine the distributions of m<sup>6</sup>A on RNA, whereas readers mediate m<sup>6</sup>A-dependent functions. m<sup>6</sup>A has also been shown to mediate a structural switch termed m<sup>6</sup>A switch<ref>{{Cite journal|last=Liu|first=Nian|last2=Dai|first2=Qing|last3=Zheng|first3=Guanqun|last4=He|first4=Chuan|last5=Parisien|first5=Marc|last6=Pan|first6=Tao|date=2015-02-26|title=N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&amp;cmd=Retrieve&amp;db=PubMed&amp;list_uids=25719671&amp;dopt=Abstract|journal=Nature|volume=518|issue=7540|pages=560–564|doi=10.1038/nature14234|issn=1476-4687|pmc=4355918|pmid=25719671}}</ref>.


== Species distribution ==
== Species distribution ==
Line 58: Line 60:
== Clinical significance ==
== Clinical significance ==


Considering the versatile functions of m<sup>6</sup>A in various physiological processes, it is thus not surprising to find links between m<sup>6</sup>A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m<sup>6</sup>A. The linkages between m<sup>6</sup>A and numerous cancer types have been indicated in reports that include stomach cancer, prostate cancer, breast cancer, pancreatic cancer, kidney cancer, mesothelioma, sarcoma, and leukaemia<ref>{{Cite journal|last=Akilzhanova|first=Ainur|last2=Nurkina|first2=Zhannur|last3=Momynaliev|first3=Kuvat|last4=Ramanculov|first4=Erlan|last5=Zhumadilov|first5=Zhaxibai|last6=Zhumadilov|first6=Zhaxybai|last7=Rakhypbekov|first7=Tolebay|last8=Hayashida|first8=Naomi|last9=Nakashima|first9=Masahiro|date=2013-09-01|title=Genetic profile and determinants of homocysteine levels in Kazakhstan patients with breast cancer|url=https://www.ncbi.nlm.nih.gov/pubmed/24023349|journal=Anticancer Research|volume=33|issue=9|pages=4049–4059|issn=1791-7530|pmid=24023349}}</ref><ref>{{Cite journal|last=Reddy|first=S. M.|last2=Sadim|first2=M.|last3=Li|first3=J.|last4=Yi|first4=N.|last5=Agarwal|first5=S.|last6=Mantzoros|first6=C. S.|last7=Kaklamani|first7=V. G.|date=2013-08-20|title=Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer|url=http://www.nature.com/bjc/journal/v109/n4/full/bjc2013441a.html|journal=British Journal of Cancer|language=en|volume=109|issue=4|pages=872–881|doi=10.1038/bjc.2013.441|issn=0007-0920|pmc=3749587|pmid=23922112}}</ref><ref>{{Cite journal|last=Heiliger|first=Katrin-Janine|last2=Hess|first2=Julia|last3=Vitagliano|first3=Donata|last4=Salerno|first4=Paolo|last5=Braselmann|first5=Herbert|last6=Salvatore|first6=Giuliana|last7=Ugolini|first7=Clara|last8=Summerer|first8=Isolde|last9=Bogdanova|first9=Tatjana|date=2012-06-01|title=Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice|url=http://erc.endocrinology-journals.org/content/19/3/409|journal=Endocrine-Related Cancer|language=en|volume=19|issue=3|pages=409–421|doi=10.1530/ERC-11-0387|issn=1351-0088|pmid=22454401}}</ref><ref>{{Cite journal|last=Ortega|first=Angeles|last2=Niksic|first2=Martina|last3=Bachi|first3=Angela|last4=Wilm|first4=Matthias|last5=Sánchez|first5=Lucas|last6=Hastie|first6=Nicholas|last7=Valcárcel|first7=Juan|date=2003-01-31|title=Biochemical Function of Female-Lethal (2)D/Wilms' Tumor Suppressor-1-associated Proteins in Alternative Pre-mRNA Splicing|url=http://www.jbc.org/content/278/5/3040|journal=Journal of Biological Chemistry|language=en|volume=278|issue=5|pages=3040–3047|doi=10.1074/jbc.M210737200|issn=0021-9258|pmid=12444081}}</ref><ref>{{Cite journal|last=Jin|first=Du-Il|last2=Lee|first2=Sang Weon|last3=Han|first3=Myoung-Eun|last4=Kim|first4=Hyun-Jung|last5=Seo|first5=Seon-Ae|last6=Hur|first6=Gi-Yeong|last7=Jung|first7=Shin|last8=Kim|first8=Bong-Seon|last9=Oh|first9=Sae-Ock|date=2012-12-01|title=Expression and roles of Wilms' tumor 1-associating protein in glioblastoma|url=http://onlinelibrary.wiley.com/doi/10.1111/cas.12022/abstract|journal=Cancer Science|language=en|volume=103|issue=12|pages=2102–2109|doi=10.1111/cas.12022|issn=1349-7006}}</ref><ref>{{Cite journal|last=Lin|first=Yingsong|last2=Ueda|first2=Junko|last3=Yagyu|first3=Kiyoko|last4=Ishii|first4=Hiroshi|last5=Ueno|first5=Makoto|last6=Egawa|first6=Naoto|last7=Nakao|first7=Haruhisa|last8=Mori|first8=Mitsuru|last9=Matsuo|first9=Keitaro|date=2013-01-01|title=Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case–control study in Japan|url=http://dx.doi.org/10.1186/1471-2407-13-337|journal=BMC Cancer|volume=13|pages=337|doi=10.1186/1471-2407-13-337|issn=1471-2407|pmc=3716552|pmid=23835106}}</ref><ref>{{Cite journal|last=Casalegno-Garduño|first=R.|last2=Schmitt|first2=A.|last3=Wang|first3=X.|last4=Xu|first4=X.|last5=Schmitt|first5=M.|title=Wilms' Tumor 1 as a Novel Target for Immunotherapy of Leukemia|url=https://dx.doi.org/10.1016/j.transproceed.2010.07.034|journal=Transplantation Proceedings|volume=42|issue=8|pages=3309–3311|doi=10.1016/j.transproceed.2010.07.034}}</ref><ref>{{Cite journal|last=Linnebacher|first=Michael|last2=Wienck|first2=Anne|last3=Boeck|first3=Inga|last4=Klar|first4=Ernst|date=2010-03-18|title=Identification of an MSI-H Tumor-Specific Cytotoxic T Cell Epitope Generated by the (−1) Frame ofU79260(FTO)|url=https://dx.doi.org/10.1155/2010/841451|journal=Journal of Biomedicine and Biotechnology|language=en|volume=2010|pages=1–6|doi=10.1155/2010/841451|issn=1110-7243|pmc=2842904|pmid=20339516}}</ref><ref>{{Cite journal|last=Machiela|first=Mitchell J.|last2=Lindström|first2=Sara|last3=Allen|first3=Naomi E.|last4=Haiman|first4=Christopher A.|last5=Albanes|first5=Demetrius|last6=Barricarte|first6=Aurelio|last7=Berndt|first7=Sonja I.|last8=Bueno-de-Mesquita|first8=H. Bas|last9=Chanock|first9=Stephen|date=2012-12-15|title=Association of Type 2 Diabetes Susceptibility Variants With Advanced Prostate Cancer Risk in the Breast and Prostate Cancer Cohort Consortium|url=http://aje.oxfordjournals.org/content/176/12/1121|journal=American Journal of Epidemiology|language=en|volume=176|issue=12|pages=1121–1129|doi=10.1093/aje/kws191|issn=0002-9262|pmc=3571230|pmid=23193118}}</ref><ref>{{Cite journal|last=Long|first=Jirong|last2=Zhang|first2=Ben|last3=Signorello|first3=Lisa B.|last4=Cai|first4=Qiuyin|last5=Deming-Halverson|first5=Sandra|last6=Shrubsole|first6=Martha J.|last7=Sanderson|first7=Maureen|last8=Dennis|first8=Joe|last9=Michailiou|first9=Kyriaki|date=2013-04-08|title=Evaluating Genome-Wide Association Study-Identified Breast Cancer Risk Variants in African-American Women|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058350|journal=PLOS ONE|volume=8|issue=4|pages=e58350|doi=10.1371/journal.pone.0058350|issn=1932-6203|pmc=3620157|pmid=23593120}}</ref><ref>{{Cite journal|last=Kaklamani|first=Virginia|last2=Yi|first2=Nengjun|last3=Sadim|first3=Maureen|last4=Siziopikou|first4=Kalliopi|last5=Zhang|first5=Kui|last6=Xu|first6=Yanfei|last7=Tofilon|first7=Sarah|last8=Agarwal|first8=Surbhi|last9=Pasche|first9=Boris|date=2011-01-01|title=The role of the fat mass and obesity associated gene (FTO) in breast cancer risk|url=http://dx.doi.org/10.1186/1471-2350-12-52|journal=BMC Medical Genetics|volume=12|pages=52|doi=10.1186/1471-2350-12-52|issn=1471-2350|pmc=3089782|pmid=21489227}}</ref><ref>{{Cite journal|last=Pierce|first=Brandon L.|last2=Austin|first2=Melissa A.|last3=Ahsan|first3=Habibul|date=2011-03-29|title=Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data|url=http://link.springer.com/article/10.1007/s10552-011-9760-5|journal=Cancer Causes & Control|language=en|volume=22|issue=6|pages=877–883|doi=10.1007/s10552-011-9760-5|issn=0957-5243}}</ref>. The impacts of m<sup>6</sup>A on cancer cell proliferation might be much more profound with more data emerging. The depletion of METTL3 is known to cause apoptosis of cancer cells and reduce invasiveness of cancer cells<ref>{{Cite book|url=http://link.springer.com/chapter/10.1007/b106365|title=Fine-Tuning of RNA Functions by Modification and Editing|last=Bokar|first=Joseph A.|date=2005-01-01|publisher=Springer Berlin Heidelberg|isbn=9783540244950|editor-last=Grosjean|editor-first=Henri|series=Topics in Current Genetics|pages=141–177|language=en|doi=10.1007/b106365}}</ref><ref>{{Cite journal|last=Lin|first=Shuibin|last2=Choe|first2=Junho|last3=Du|first3=Peng|last4=Triboulet|first4=Robinson|last5=Gregory|first5=Richard I.|date=2016-05-05|title=The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells|url=https://www.ncbi.nlm.nih.gov/pubmed/27117702|journal=Molecular Cell|volume=62|issue=3|pages=335–345|doi=10.1016/j.molcel.2016.03.021|issn=1097-4164|pmc=4860043|pmid=27117702}}</ref>, while the activation of ALKBH5 by hypoxia was shown to cause cancer stem cell enrichment<ref>{{Cite journal|last=Zhang|first=Chuanzhao|last2=Samanta|first2=Debangshu|last3=Lu|first3=Haiquan|last4=Bullen|first4=John W.|last5=Zhang|first5=Huimin|last6=Chen|first6=Ivan|last7=He|first7=Xiaoshun|last8=Semenza|first8=Gregg L.|date=2016-04-05|title=Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA|url=http://www.pnas.org/content/113/14/E2047|journal=Proceedings of the National Academy of Sciences|language=en|volume=113|issue=14|pages=E2047–E2056|doi=10.1073/pnas.1602883113|issn=0027-8424|pmc=4833258|pmid=27001847}}</ref>. m<sup>6</sup>A has also been indicated in the regulation of energy homeostasis and obesity, as FTO is a key regulatory gene for energy metabolism and obesity. SNPs of ''FTO'' have been shown to associate with body mass index in human populations and occurrence of obesity and diabetes<ref>{{Cite journal|last=Loos|first=Ruth J. F.|last2=Yeo|first2=Giles S. H.|title=The bigger picture of FTO—the first GWAS-identified obesity gene|url=https://dx.doi.org/10.1038/nrendo.2013.227|journal=Nature Reviews Endocrinology|volume=10|issue=1|pages=51–61|doi=10.1038/nrendo.2013.227|pmc=4188449|pmid=24247219}}</ref><ref>{{Cite journal|last=Frayling|first=Timothy M.|last2=Timpson|first2=Nicholas J.|last3=Weedon|first3=Michael N.|last4=Zeggini|first4=Eleftheria|last5=Freathy|first5=Rachel M.|last6=Lindgren|first6=Cecilia M.|last7=Perry|first7=John R. B.|last8=Elliott|first8=Katherine S.|last9=Lango|first9=Hana|date=2007-05-11|title=A Common Variant in the FTO Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity|url=http://science.sciencemag.org/content/316/5826/889|journal=Science|language=en|volume=316|issue=5826|pages=889–894|doi=10.1126/science.1141634|issn=0036-8075|pmc=2646098|pmid=17434869}}</ref><ref>{{Cite journal|last=Wang|first=Lina|last2=Yu|first2=Qing|last3=Xiong|first3=Yan|last4=Liu|first4=Linfei|last5=Zhang|first5=Xuening|last6=Zhang|first6=Zhen|last7=Wu|first7=Jianru|last8=Wang|first8=Bei|title=Variant rs1421085 in the FTO gene contribute childhood obesity in Chinese children aged 3–6years|url=https://dx.doi.org/10.1016/j.orcp.2011.12.007|journal=Obesity Research & Clinical Practice|volume=7|issue=1|pages=e14–e22|doi=10.1016/j.orcp.2011.12.007}}</ref><ref>{{Cite journal|last=Kalnina|first=Ineta|last2=Zaharenko|first2=Linda|last3=Vaivade|first3=Iveta|last4=Rovite|first4=Vita|last5=Nikitina-Zake|first5=Liene|last6=Peculis|first6=Raitis|last7=Fridmanis|first7=Davids|last8=Geldnere|first8=Kristine|last9=Jacobsson|first9=Josefin A.|date=2013-09-25|title=Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes|url=http://www.sciencedirect.com/science/article/pii/S0378111913008470|journal=Gene|volume=527|issue=2|pages=462–468|doi=10.1016/j.gene.2013.06.079}}</ref><ref>{{Cite journal|last=Karra|first=Efthimia|last2=O’Daly|first2=Owen G.|last3=Choudhury|first3=Agharul I.|last4=Yousseif|first4=Ahmed|last5=Millership|first5=Steven|last6=Neary|first6=Marianne T.|last7=Scott|first7=William R.|last8=Chandarana|first8=Keval|last9=Manning|first9=Sean|date=2013-08-01|title=A link between FTO, ghrelin, and impaired brain food-cue responsivity|url=https://dx.doi.org/10.1172/JCI44403|journal=Journal of Clinical Investigation|language=en|volume=123|issue=8|pages=3539–3551|doi=10.1172/jci44403|issn=0021-9738}}</ref>. The influence of FTO on pre-adipocyte differentiation has been suggested<ref>{{Cite journal|last=Zhao|first=Xu|last2=Yang|first2=Ying|last3=Sun|first3=Bao-Fa|last4=Shi|first4=Yue|last5=Yang|first5=Xin|last6=Xiao|first6=Wen|last7=Hao|first7=Ya-Juan|last8=Ping|first8=Xiao-Li|last9=Chen|first9=Yu-Sheng|date=2014-12-01|title=FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis|url=http://www.nature.com/cr/journal/v24/n12/full/cr2014151a.html|journal=Cell Research|language=en|volume=24|issue=12|pages=1403–1419|doi=10.1038/cr.2014.151|issn=1001-0602|pmc=4260349|pmid=25412662}}</ref><ref>{{Cite journal|last=Merkestein|first=Myrte|last2=Laber|first2=Samantha|last3=McMurray|first3=Fiona|last4=Andrew|first4=Daniel|last5=Sachse|first5=Gregor|last6=Sanderson|first6=Jeremy|last7=Li|first7=Mengdi|last8=Usher|first8=Samuel|last9=Sellayah|first9=Dyan|date=2015-04-17|title=FTO influences adipogenesis by regulating mitotic clonal expansion|url=https://dx.doi.org/10.1038/ncomms7792|journal=Nature Communications|language=en|volume=6|doi=10.1038/ncomms7792|issn=2041-1723|pmc=4410642|pmid=25881961}}</ref><ref>{{Cite journal|last=Zhang|first=Meizi|last2=Zhang|first2=Ying|last3=Ma|first3=Jun|last4=Guo|first4=Feima|last5=Cao|first5=Qian|last6=Zhang|first6=Yu|last7=Zhou|first7=Bin|last8=Chai|first8=Jijie|last9=Zhao|first9=Wenqing|date=2015-07-28|title=The Demethylase Activity of FTO (Fat Mass and Obesity Associated Protein) Is Required for Preadipocyte Differentiation|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133788|journal=PLOS ONE|volume=10|issue=7|pages=e0133788|doi=10.1371/journal.pone.0133788|issn=1932-6203|pmc=4517749|pmid=26218273}}</ref>. The connection between m<sup>6</sup>A and neuronal disorders has also been studied. For instance, neurodegenerative diseases may be affected by m<sup>6</sup>A as the cognate dopamine signalling was shown to be dependent on FTO and correct m<sup>6</sup>A methylation on key signalling transcripts<ref>{{Cite journal|last=Hess|first=Martin E|last2=Hess|first2=Simon|last3=Meyer|first3=Kate D|last4=Verhagen|first4=Linda A W|last5=Koch|first5=Linda|last6=Brönneke|first6=Hella S|last7=Dietrich|first7=Marcelo O|last8=Jordan|first8=Sabine D|last9=Saletore|first9=Yogesh|title=The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry|url=https://dx.doi.org/10.1038/nn.3449|journal=Nature Neuroscience|volume=16|issue=8|pages=1042–1048|doi=10.1038/nn.3449}}</ref>. The mutations in HNRNPA2B1, a potential reader of m<sup>6</sup>A, have been known to cause neurodegeneration<ref>{{Cite journal|last=Kim|first=Hong Joo|last2=Kim|first2=Nam Chul|last3=Wang|first3=Yong-Dong|last4=Scarborough|first4=Emily A.|last5=Moore|first5=Jennifer|last6=Diaz|first6=Zamia|last7=MacLea|first7=Kyle S.|last8=Freibaum|first8=Brian|last9=Li|first9=Songqing|title=Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS|url=https://dx.doi.org/10.1038/nature11922|journal=Nature|volume=495|issue=7442|pages=467–473|doi=10.1038/nature11922|pmc=3756911|pmid=23455423}}</ref>.
The obesity risk gene, [[FTO gene|''FTO'']], encodes the first identified m<sup>6</sup>A demethylase.<ref name="Meyer_2012"/><ref name="Jia_2011">{{cite journal | vauthors = Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang YG, He C | title = N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO | journal = Nature Chemical Biology | volume = 7 | issue = 12 | pages = 885–7 | date = October 2011 | pmid = 22002720 | pmc = 3218240 | doi = 10.1038/nchembio.687 }}</ref> [[FTO gene|''FTO'']] mutations have been associated with increased risk for obesity and type 2 diabetes, which implicates m<sup>6</sup>A in important physiological pathways related to human disease. [[FTO gene|FTO]] [[Gene knockdown|knockdown]] with [[siRNA]] leads to increased amounts of m<sup>6</sup>A in poly(A) RNA,<ref name="Dominissini_2012"/> whereas [[overexpression]] of [[FTO gene|FTO]] results in decreased amounts of m<sup>6</sup>A in human cells.<ref name="Meyer_2012"/> FTO partially localizes to [[nuclear speckles]],<ref name="Jia_2011"/> which supports the notion that m<sup>6</sup>A in nuclear RNA is a major physiological [[substrate (biochemistry)|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 m<sup>6</sup>A demethylase suggests that increased FTO activity in patients with ''FTO'' mutations leads to abnormally low levels of m<sup>6</sup>A in target mRNAs, which through as-yet undefined pathways contributes to the onset of obesity and related diseases.

Additionally, m<sup>6</sup>A has been reported to impact viral infections. Many RNA viruses including SV40, adenovirus, herpes virus, Rous sarcoma virus, and influenza virus have been known to contain the internal m<sup>6</sup>A methylation on virus genomic RNA<ref>{{Cite book|url=http://onlinelibrary.wiley.com/doi/10.1002/9780470123119.ch7/summary|title=Advances in Enzymology and Related Areas of Molecular Biology|last=Narayan|first=Prema|last2=Rottman|first2=Fritz M.|date=1992-01-01|publisher=John Wiley & Sons, Inc.|isbn=9780470123119|editor-last=Nord|editor-first=F. F.|pages=255–285|language=en|doi=10.1002/9780470123119.ch7/summary}}</ref>. Several more recent studies have revealed that m<sup>6</sup>A regulators govern the efficiency of infection and replication of RNA viruses such as human immunodeficiency virus (HIV)<ref>{{Cite journal|last=Tirumuru|first=Nagaraja|last2=Zhao|first2=Boxuan Simen|last3=Lu|first3=Wuxun|last4=Lu|first4=Zhike|last5=He|first5=Chuan|last6=Wu|first6=Li|title=N6-methyladenosine of HIV-1 RNA regulates viral infection and HIV-1 Gag protein expression|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961459/|journal=eLife|volume=5|doi=10.7554/eLife.15528|issn=2050-084X|pmc=4961459|pmid=27371828}}</ref><ref>{{Cite journal|last=Lichinchi|first=Gianluigi|last2=Gao|first2=Shang|last3=Saletore|first3=Yogesh|last4=Gonzalez|first4=Gwendolyn Michelle|last5=Bansal|first5=Vikas|last6=Wang|first6=Yinsheng|last7=Mason|first7=Christopher E.|last8=Rana|first8=Tariq M.|title=Dynamics of the human and viral m6A RNA methylomes during HIV-1 infection of T cells|url=http://www.nature.com/articles/nmicrobiol201611|journal=Nature Microbiology|volume=1|issue=4|doi=10.1038/nmicrobiol.2016.11}}</ref><ref>{{Cite journal|last=Kennedy|first=Edward M.|last2=Bogerd|first2=Hal P.|last3=Kornepati|first3=Anand V.R.|last4=Kang|first4=Dong|last5=Ghoshal|first5=Delta|last6=Marshall|first6=Joy B.|last7=Poling|first7=Brigid C.|last8=Tsai|first8=Kevin|last9=Gokhale|first9=Nandan S.|title=Posttranscriptional m6A Editing of HIV-1 mRNAs Enhances Viral Gene Expression|url=http://dx.doi.org/10.1016/j.chom.2016.04.002|journal=Cell Host & Microbe|volume=19|issue=5|pages=675–685|doi=10.1016/j.chom.2016.04.002|pmc=4867121|pmid=27117054}}</ref> and Zika virus (ZIKV)<ref>{{Cite journal|last=Lichinchi|first=Gianluigi|last2=Zhao|first2=Boxuan Simen|last3=Wu|first3=Yinga|last4=Lu|first4=Zhike|last5=Qin|first5=Yue|last6=He|first6=Chuan|last7=Rana|first7=Tariq M.|title=Dynamics of Human and Viral RNA Methylation during Zika Virus Infection|url=http://dx.doi.org/10.1016/j.chom.2016.10.002|journal=Cell Host & Microbe|volume=20|issue=5|pages=666–673|doi=10.1016/j.chom.2016.10.002|pmc=5155635|pmid=27773536}}</ref><ref>{{Cite journal|last=Gokhale|first=Nandan S.|last2=McIntyre|first2=Alexa B.R.|last3=McFadden|first3=Michael J.|last4=Roder|first4=Allison E.|last5=Kennedy|first5=Edward M.|last6=Gandara|first6=Jorge A.|last7=Hopcraft|first7=Sharon E.|last8=Quicke|first8=Kendra M.|last9=Vazquez|first9=Christine|title=N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection|url=http://dx.doi.org/10.1016/j.chom.2016.09.015|journal=Cell Host & Microbe|volume=20|issue=5|pages=654–665|doi=10.1016/j.chom.2016.09.015|pmc=5123813|pmid=27773535}}</ref>. These results suggest m<sup>6</sup>A and its cognate factors play crucial roles in regulating virus life cycle and host-viral interactions. 


== References ==
== References ==

Revision as of 22:14, 2 January 2017

N6-Methyladenosine
Names
IUPAC name
N-Methyladenosine
Other names
m6A
Identifiers
3D model (JSmol)
ChemSpider
  • InChI=1S/C11H15N5O4/c1-12-9-6-10(14-3-13-9)16(4-15-6)11-8(19)7(18)5(2-17)20-11/h3-5,7-8,11,17-19H,2H2,1H3,(H,12,13,14)/t5-,7-,8-,11-/m1/s1
    Key: VQAYFKKCNSOZKM-IOSLPCCCSA-N
  • InChI=1/C11H15N5O4/c1-12-9-6-10(14-3-13-9)16(4-15-6)11-8(19)7(18)5(2-17)20-11/h3-5,7-8,11,17-19H,2H2,1H3,(H,12,13,14)/t5-,7-,8-,11-/m1/s1
    Key: VQAYFKKCNSOZKM-IOSLPCCCBA
  • n2c1c(ncnc1NC)n(c2)[C@@H]3O[C@@H]([C@@H](O)[C@H]3O)CO
Properties
C11H15N5O4
Molar mass 281.272 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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] More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including METTL14[19][20], Wilms tumor 1 associated protein (WTAP)[19][21] and KIAA1429[22]. Following a 2010 speculation of m6A in mRNA being dynamic and reversible[23], the discovery of the first m6A demethylase, fat mass and obesity-associated protein (FTO) in 2011[24] confirmed this hypothesis and revitalized the interests in the study of m6A. A second m6A demethylase alkB homolog 5 (ALKBH5) was later discovered as well[25].

The biological functions of m6A are mediated through a group of RNA binding proteins that specifically recognize the methylated adenosine on RNA. These binding proteins are named m6A readers. The YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3 and YTHDC1) have been characterized as direct m6A readers and have a conserved m6A-binding pocket[14][26][27][28][29][30][31]. These m6A readers, together with m6A methyltransferases (writers) and demethylases (erasers), establish a complex mechanism of m6A regulation in which writers and erasers determine the distributions of m6A on RNA, whereas readers mediate m6A-dependent functions. m6A has also been shown to mediate a structural switch termed m6A switch[32].

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.[33]

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.[33]

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][34] 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] By integrating all m6A sequencing data, a novel database called RMBase has identified and provided ~200,000 N6-Methyladenosines (m6A) sites in the human and mouse genomes.[34]

Precise m6A mapping by m6A-CLIP/IP [35] (briefly m6A-CLIP, in multiple tissues/cultured cells of mouse and human) revealed that a majority of m6A locates in the last exon of mRNAs,[35] 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.[35] The major presence of m6A in last exon (>=70%) allows the potential for 3'UTR regulation, including alternative polyadenylation.[35]

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.[36][37]

Clinical significance

Considering the versatile functions of m6A in various physiological processes, it is thus not surprising to find links between m6A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m6A. The linkages between m6A and numerous cancer types have been indicated in reports that include stomach cancer, prostate cancer, breast cancer, pancreatic cancer, kidney cancer, mesothelioma, sarcoma, and leukaemia[38][39][40][41][42][43][44][45][46][47][48][49]. The impacts of m6A on cancer cell proliferation might be much more profound with more data emerging. The depletion of METTL3 is known to cause apoptosis of cancer cells and reduce invasiveness of cancer cells[50][51], while the activation of ALKBH5 by hypoxia was shown to cause cancer stem cell enrichment[52]. m6A has also been indicated in the regulation of energy homeostasis and obesity, as FTO is a key regulatory gene for energy metabolism and obesity. SNPs of FTO have been shown to associate with body mass index in human populations and occurrence of obesity and diabetes[53][54][55][56][57]. The influence of FTO on pre-adipocyte differentiation has been suggested[58][59][60]. The connection between m6A and neuronal disorders has also been studied. For instance, neurodegenerative diseases may be affected by m6A as the cognate dopamine signalling was shown to be dependent on FTO and correct m6A methylation on key signalling transcripts[61]. The mutations in HNRNPA2B1, a potential reader of m6A, have been known to cause neurodegeneration[62].

Additionally, m6A has been reported to impact viral infections. Many RNA viruses including SV40, adenovirus, herpes virus, Rous sarcoma virus, and influenza virus have been known to contain the internal m6A methylation on virus genomic RNA[63]. Several more recent studies have revealed that m6A regulators govern the efficiency of infection and replication of RNA viruses such as human immunodeficiency virus (HIV)[64][65][66] and Zika virus (ZIKV)[67][68]. These results suggest m6A and its cognate factors play crucial roles in regulating virus life cycle and host-viral interactions. 

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