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

By G. Zheng, J. Dahl, Y. Niu, P. Fedorcsak, Chunmin Huang, Charles J. Li, C. Vågbø, Yue Shi, Wen-ling Wang, Shu-hui Song and 18 more. Molecules and Cells, 2012

3,110 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2407ce031a0aaead6447709089fbff973a577e83

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Citations in the corpus

Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “The predicted role of m6A as a splicing regulator is initially based on the early observations that m6A sites are concentrated in the introns of pre-mRNAs and were more abundant in pre-mRNAs than in mature mRNA.132–134 One previous study indicated that pre‑mRNAs are methylated at a level of ~4 m6A r”
N6-methyladenosine Modulates Messenger RNA Translation Efficiency (2015, positive): “, 2014b), demethylases (‘‘eraser’’; Jia et al., 2011; Zheng et al., 2013), and mA-specific binding proteins (‘‘reader’’; Dominissini et al.”
RNA-methylation-dependent RNA processing controls the speed of the circadian clock. (2013, positive): “Recently, two m 6 A demethylases were identified (Jia et al., 2011; Zheng et al., 2013), supporting the possibility of dynamically regulated m”
RNA N6‐methyladenosine methyltransferase‐like 3 promotes liver cancer progression through YTHDF2‐dependent posttranscriptional silencing of SOCS2 (2018, background): “The reversible process is conducted by m6A eraser fat mass and obesity-associated protein (FTO) and alkB homologue 5 (ALKBH5).((17,18)) While ALKBH5 catalyzes the direct removal of m6A, FTO can sequentially oxidize m6A to N6hydroxymethyladeosine and N6-formyladenosine, which are moderately stable an”
RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation (2015, background): “Shortly after the discovery of FTO, ALKBH5was identified and characterized as a secondmammalianm6Ademethylase that displays distinct biological functions (Zheng et al. 2013).”
Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5 (2014, methodology): “Another member of the AlkB family, ALKBH5, was also identified as an m6A demethylase of mRNA using Fe2+ and cofactor 2OG, which together function to oxidatively remove the methyl group in m6A-containing substrates (27).”
METTL3 promotes translation in human cancer cells (2016, background): “…and stem cell self-renewal and differentiation (Batista et al., 2014; Chen et al., 2015; Fustin et al., 2013; Geula et al., 2015; Iles et al., 2013; Lin and Gregory, 2014; Wang et al., 2014c; Zhao et al., 2014; Zheng et al., 2013) (reviewed in Meyer and Jaffrey, 2014; Yue et al., 2015).”
RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “A set of m(6)A demethylases, such as FTO and ALKBH5, can remove m(6)A modification from RNA as m(6)A erasers and thus keep m(6)A modification in a dynamic balance.(6,7,17) Members of the YT521-B homology (YTH) domain family of proteins, including YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2, have been”