ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility

Guanqun Zheng, John Arne Dah, Yamei Niu, Peter Fedorcsak, Chun-Min Huang, Charles J. Li, Cathrine B. Vagbo, Yue Shi, Wen-Ling Wang, Shu-Hui Song, Zhike Lu, Ralph P.G. Bosmans, Qing Dai, Ya-Juan Hao, Xin Yang, Wen-Ming Zhao, Wei-Min Tong, Xiu-Jie Wang, Florian Bogdan, Kari Furu, Ye Fu, Guifang Jia, Xu Zhao, Jun Liu, Hans E. Krokan, Arne Klungland, Yun-Gui Yang, Chuan He

N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m6A in mRNA in vitro and in vivo. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice have increased m6A in mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m6A modification has fundamental and broad functions in mammalian cells.

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