Please use this identifier to cite or link to this item: https://doi.org/10.1038/srep25677
Title: N 6 -Methyladenosine: A conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5
Authors: Zou, S
Toh, J.D.W
Wong, K.H.Q
Gao, Y.-G
Hong, W 
Woon, E.C.Y 
Keywords: adenosine
ALKBH5 protein, human
alkylated DNA repair protein alkB homolog 5
alpha ketoglutarate dependent dioxygenase FTO
FTO protein, human
N(6)-methyladenosine
RNA
analogs and derivatives
biocatalysis
chemistry
consensus sequence
demethylation
enzyme specificity
human
metabolism
nucleotide sequence
oxidation reduction reaction
protein conformation
protein motif
RNA stability
thermodynamics
Adenosine
AlkB Homolog 5, RNA Demethylase
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
Amino Acid Motifs
Base Sequence
Biocatalysis
Consensus Sequence
Demethylation
Humans
Oxidation-Reduction
Protein Conformation
RNA
RNA Stability
Substrate Specificity
Thermodynamics
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Zou, S, Toh, J.D.W, Wong, K.H.Q, Gao, Y.-G, Hong, W, Woon, E.C.Y (2016). N 6 -Methyladenosine: A conformational marker that regulates the substrate specificity of human demethylases FTO and ALKBH5. Scientific Reports 6 : 25677. ScholarBank@NUS Repository. https://doi.org/10.1038/srep25677
Abstract: N 6 -Methyladenosine (m6A) is currently one of the most intensively studied post-transcriptional modifications in RNA. Due to its critical role in epigenetics and physiological links to several human diseases, it is also of tremendous biological and medical interest. The m6A mark is dynamically reversed by human demethylases FTO and ALKBH5, however the mechanism by which these enzymes selectively recognise their target transcripts remains unclear. Here, we report combined biophysical and biochemical studies on the specificity determinants of m6A demethylases, which led to the identification of an m6A-mediated substrate discrimination mechanism. Our results reveal that m6A itself serves as a "conformational marker", which induces different conformational outcomes in RNAs depending on sequence context. This critically impacts its interactions with several m6A-recognising proteins, including FTO and ALKBH5. Remarkably, through the RNA-remodelling effects of m6A, the demethylases were able to discriminate substrates with very similar nucleotide sequences. Our findings provide novel insights into the biological functions of m6A modifications. The mechanism identified in this work is likely of significance to other m6A-recognising proteins.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/174971
ISSN: 20452322
DOI: 10.1038/srep25677
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