Jiao Xinfu, Doamekpor Selom K, Bird Jeremy G, Nickels Bryce E, Tong Liang, Hart Ronald P, Kiledjian Megerditch
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Cell. 2017 Mar 9;168(6):1015-1027.e10. doi: 10.1016/j.cell.2017.02.019.
Eukaryotic mRNAs generally possess a 5' end N7 methyl guanosine (mG) cap that promotes their translation and stability. However, mammalian mRNAs can also carry a 5' end nicotinamide adenine dinucleotide (NAD) cap that, in contrast to the mG cap, does not support translation but instead promotes mRNA decay. The mammalian and fungal noncanonical DXO/Rai1 decapping enzymes efficiently remove NAD caps, and cocrystal structures of DXO/Rai1 with 3'-NADP illuminate the molecular mechanism for how the "deNADding" reaction produces NAD and 5' phosphate RNA. Removal of DXO from cells increases NAD-capped mRNA levels and enables detection of NAD-capped intronic small nucleolar RNAs (snoRNAs), suggesting NAD caps can be added to 5'-processed termini. Our findings establish NAD as an alternative mammalian RNA cap and DXO as a deNADding enzyme modulating cellular levels of NAD-capped RNAs. Collectively, these data reveal that mammalian RNAs can harbor a 5' end modification distinct from the classical mG cap that promotes rather than inhibits RNA decay.
真核生物的信使核糖核酸（mRNA）通常在5'端具有N7甲基鸟苷（mG）帽结构，该结构可促进其翻译和稳定性。然而，哺乳动物的mRNA也可能携带5'端烟酰胺腺嘌呤二核苷酸（NAD）帽结构，与mG帽不同的是，NAD帽不支持翻译，反而会促进mRNA降解。哺乳动物和真菌的非典型DXO/Rai1去帽酶能够有效地去除NAD帽，DXO/Rai1与3'-NADP的共晶体结构揭示了“去NAD化”反应如何产生NAD和5'磷酸化RNA的分子机制。从细胞中去除DXO会增加NAD帽化的mRNA水平，并能够检测到NAD帽化的内含子小核仁RNA（snoRNA），这表明NAD帽可以添加到5'加工末端。我们的研究结果确定NAD是一种替代的哺乳动物RNA帽，DXO是一种调节NAD帽化RNA细胞水平的去NAD化酶。总的来说，这些数据表明哺乳动物RNA可以具有一种不同于经典mG帽的5'端修饰，这种修饰促进而非抑制RNA降解。
