ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

1. Mol Cell. 2013 Jan 10;49(1):18-29. doi: 10.1016/j.molcel.2012.10.015. Epub 2012 Nov 21. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Zheng G(1), Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG, He C. Author information: (1)Department of Chemistry, Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Comment in RNA Biol. 2013 Jun;10(6):915-8. doi: 10.4161/rna.24711. 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. Copyright © 2013 Elsevier Inc. All rights reserved. DOI: 10.1016/j.molcel.2012.10.015 PMCID: PMC3646334 PMID: 23177736 [Indexed for MEDLINE]