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

Mol Cell. 2013 Jan 10;49(1):18-29. doi: 10.1016/j.molcel.2012.10.015. Epub 2012 Nov 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AlkB Homolog 5, RNA Demethylase
  • Animals
  • Base Sequence
  • Cell Nucleus / metabolism
  • Dioxygenases / chemistry
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Infertility, Male / enzymology
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Organ Size
  • Oxidoreductases, N-Demethylating / chemistry
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism*
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA Processing, Post-Transcriptional*
  • RNA, Messenger / chemistry
  • RNA, Messenger / metabolism*
  • Spermatogenesis / genetics
  • Testis / enzymology
  • Testis / pathology
  • Transcriptome

Substances

  • Membrane Proteins
  • RNA, Messenger
  • Dioxygenases
  • ALKBH5 protein, human
  • AlkB Homolog 5, RNA Demethylase
  • Oxidoreductases, N-Demethylating
  • SRPK1 protein, human
  • Protein-Serine-Threonine Kinases