2011
DOI: 10.1038/nchembio.687
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N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO

Abstract: We report here that FTO (fat mass and obesity-associated protein) exhibits efficient oxidative demethylation activity of abundant N6-methyladenosine (m6A) residues in RNA in vitro. FTO knockdown with siRNA led to an increased level of m6A in mRNA, whereas overexpression of FTO resulted in a decreased level of m6A in human cells. We further show that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.

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Cited by 3,273 publications
(3,677 citation statements)
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References 24 publications
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“…While the Ten‐Eleven Translocation (TET) protein family of dioxygenases primarily mediates oxidation of m 5 C in nuclear DNA and has also been implicated in histone modification, most of the members of the AlkB‐like Fe(II)/alpha‐ketoglutarate‐dependent dioxygenases (ALKBH) have been shown to act on RNA (reviewed in Shen et al , 2014; Fedeles et al , 2015; Li et al , 2015; Ougland et al , 2015). These include FTO (ALKBH9) that is implicated together with ALKBH5 in the oxidative removal of several modifications including 6‐methyladenosine (m 6 A) from RNA and ALKBH8 that is involved in the generation of 5‐methoxycarbonylmethyluridine (mcm 5 U) in cytoplasmic tRNAs (Fu et al , 2010a,b; Songe‐Møller et al , 2010; Jia et al , 2011; Thalhammer et al , 2011; Berulava et al , 2013; Zheng et al , 2013). So far, only ALKBH7, which was suggested to act on protein substrates during necrosis (Fu et al , 2013; Solberg et al , 2013; Wang et al , 2014), and ALKBH1/ABH1 have been reported to localise to mitochondria; however, the cellular localisation of ABH1 has been a matter of debate (Pan et al , 2008; Westbye et al , 2008; Ougland et al , 2012).…”
Section: Resultsmentioning
confidence: 99%
“…While the Ten‐Eleven Translocation (TET) protein family of dioxygenases primarily mediates oxidation of m 5 C in nuclear DNA and has also been implicated in histone modification, most of the members of the AlkB‐like Fe(II)/alpha‐ketoglutarate‐dependent dioxygenases (ALKBH) have been shown to act on RNA (reviewed in Shen et al , 2014; Fedeles et al , 2015; Li et al , 2015; Ougland et al , 2015). These include FTO (ALKBH9) that is implicated together with ALKBH5 in the oxidative removal of several modifications including 6‐methyladenosine (m 6 A) from RNA and ALKBH8 that is involved in the generation of 5‐methoxycarbonylmethyluridine (mcm 5 U) in cytoplasmic tRNAs (Fu et al , 2010a,b; Songe‐Møller et al , 2010; Jia et al , 2011; Thalhammer et al , 2011; Berulava et al , 2013; Zheng et al , 2013). So far, only ALKBH7, which was suggested to act on protein substrates during necrosis (Fu et al , 2013; Solberg et al , 2013; Wang et al , 2014), and ALKBH1/ABH1 have been reported to localise to mitochondria; however, the cellular localisation of ABH1 has been a matter of debate (Pan et al , 2008; Westbye et al , 2008; Ougland et al , 2012).…”
Section: Resultsmentioning
confidence: 99%
“…The abundance of m6A has been shown to be approximately 0.1–0.4% of the total adenosine residues in cellular mRNA, and the average content of m6A has been estimated to be three to five residues per mammalian mRNA 10. The m6A methylation is formed during nascent pre‐mRNA processing by a methyltransferase complex consisting of METTL3, METTL14 and WTAP and removed by FTO and ALKBH5 37, 38, 39, 40, 41. This modification plays important roles in neuronal disorders, immune response, obesity and cancer 42.…”
Section: Discussionmentioning
confidence: 99%
“…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). Reduced levels of m 6 A also affect circadian period (Fustin et al ., 2013) and are critical for stem cell differentiation in mammals (Geula et al ., 2015).…”
Section: Introductionmentioning
confidence: 99%