title: ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
abstract: N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A 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 m(6)A 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 m(6)A modification has fundamental and broad functions in mammalian cells.
authors.affiliation: Department of Chemistry, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Guanqun
authors.initials: G
authors.lastname: Zheng
authors.forename: John Arne
authors.initials: JA
authors.lastname: Dahl
authors.forename: Yamei
authors.initials: Y
authors.lastname: Niu
authors.forename: Peter
authors.initials: P
authors.lastname: Fedorcsak
authors.forename: Chun-Min
authors.initials: CM
authors.lastname: Huang
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Li
authors.forename: Cathrine B
authors.initials: CB
authors.lastname: Vågbø
authors.forename: Yue
authors.initials: Y
authors.lastname: Shi
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Wang
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Song
authors.forename: Zhike
authors.initials: Z
authors.lastname: Lu
authors.forename: Ralph P G
authors.initials: RP
authors.lastname: Bosmans
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.forename: Ya-Juan
authors.initials: YJ
authors.lastname: Hao
authors.forename: Xin
authors.initials: X
authors.lastname: Yang
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Zhao
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Tong
authors.forename: Xiu-Jie
authors.initials: XJ
authors.lastname: Wang
authors.forename: Florian
authors.initials: F
authors.lastname: Bogdan
authors.forename: Kari
authors.initials: K
authors.lastname: Furu
authors.forename: Ye
authors.initials: Y
authors.lastname: Fu
authors.forename: Guifang
authors.initials: G
authors.lastname: Jia
authors.forename: Xu
authors.initials: X
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.forename: Yun-Gui
authors.initials: YG
authors.lastname: Yang
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000071502:AlkB Homolog 5, RNA Demethylase; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D049308:Dioxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D013091:Spermatogenesis / Q000235:genetics; D013737:Testis / Q000201:enzymology / Q000473:pathology; D059467:Transcriptome
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D049308:Dioxygenases; C559920:ALKBH5 protein, human; D000071502:AlkB Homolog 5, RNA Demethylase; D010089:Oxidoreductases, N-Demethylating; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases