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

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• 作者：Guanqun Zheng¹ ; ¹¹ ; John Arne Dahl³ ; ¹¹ ; Yamei Niu² ; ¹¹ ; Peter Fedorcsak⁴ ; Chun-Min Huang² ; Charles J. Li¹ ; Cathrine B. V&aring ; gbø ; ⁶ ; Yue Shi² ; ⁷ ; Wen-Ling Wang² ; ⁷ ; Shu-Hui Song⁵ ; Zhike Lu¹ ; Ralph P.G. Bosmans¹ ; Qing Dai¹ ; Ya-Juan Hao² ; ⁷ ; Xin Yang² ; ⁷ ; Wen-Ming Zhao⁵ ; Wei-Min Tong⁸ ; Xiu-Jie Wang⁹ ; Florian Bogdan³ ; Kari Furu³ ; Ye Fu¹ ; Guifang Jia¹ ; Xu Zhao² ; ⁷ ; Jun Liu¹⁰ ; Hans E. Krokan⁶ ; Arne Klungland³ ; ^{arne.klungland@rr-research.no} ; Yun-Gui Yang² ; ⁷ ; ^{ygyang@big.ac.cn} ; Chuan He¹ ; ^{chuanhe@uchicago.edu}
• 刊名：Molecular Cell
• 出版年：2013
• 出版时间：10 January, 2013
• 年：2013
• 卷：49
• 期：1
• 页码：18-29
• 全文大小：1611 K

文摘

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Summary

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 p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m⁶A modification has fundamental and broad functions in mammalian cells.