Mauer Jan, Luo Xiaobing, Blanjoie Alexandre, Jiao Xinfu, Grozhik Anya V, Patil Deepak P, Linder Bastian, Pickering Brian F, Vasseur Jean-Jacques, Chen Qiuying, Gross Steven S, Elemento Olivier, Debart Françoise, Kiledjian Megerditch, Jaffrey Samie R
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York 10065, USA.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.
Nature. 2017 Jan 19;541(7637):371-375. doi: 10.1038/nature21022. Epub 2016 Dec 21.
Internal bases in mRNA can be subjected to modifications that influence the fate of mRNA in cells. One of the most prevalent modified bases is found at the 5' end of mRNA, at the first encoded nucleotide adjacent to the 7-methylguanosine cap. Here we show that this nucleotide, N,2'-O-dimethyladenosine (mA), is a reversible modification that influences cellular mRNA fate. Using a transcriptome-wide map of mA we find that mA-initiated transcripts are markedly more stable than mRNAs that begin with other nucleotides. We show that the enhanced stability of mA-initiated transcripts is due to resistance to the mRNA-decapping enzyme DCP2. Moreover, we find that mA is selectively demethylated by fat mass and obesity-associated protein (FTO). FTO preferentially demethylates mA rather than N-methyladenosine (mA), and reduces the stability of mA mRNAs. Together, these findings show that the methylation status of mA in the 5' cap is a dynamic and reversible epitranscriptomic modification that determines mRNA stability.
信使核糖核酸（mRNA）中的内部碱基可发生修饰，从而影响其在细胞中的命运。最常见的修饰碱基之一位于mRNA的5'端，即与7-甲基鸟苷帽相邻的第一个编码核苷酸处。我们在此表明，该核苷酸N，2'-O-二甲基腺苷（mA）是一种可逆修饰，可影响细胞内mRNA的命运。通过绘制全转录组范围的mA图谱，我们发现以mA起始的转录本比以其他核苷酸起始的mRNA明显更稳定。我们表明，以mA起始的转录本稳定性增强是由于对mRNA去帽酶DCP2具有抗性。此外，我们发现mA可被脂肪量和肥胖相关蛋白（FTO）选择性去甲基化。FTO优先使mA而非N-甲基腺苷（m6A）去甲基化，并降低mA mRNA的稳定性。这些发现共同表明，5'帽中mA的甲基化状态是一种动态且可逆的表观转录组修饰，可决定mRNA的稳定性。
