Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1α (HIF-1α).
Human 2-oxoglutarate oxygenases catalyse a range of biological oxidations including the demethylation of histone and nucleic acid substrates and the hydroxylation of proteins and small molecules. Some of these processes are centrally involved in regulation of cellular responses to hypoxia. The ALKBH proteins are a sub-family of 2OG oxygenases that are defined by homology to the Escherichia coli DNA-methylation repair enzyme AlkB. Here we report evidence that ALKBH5 is probably unique amongst the ALKBH genes in being a direct transcriptional target of hypoxia inducible factor-1 (HIF-1) and is induced by hypoxia in a range of cell types. We show that purified recombinant ALKBH5 is a bona fide 2OG oxygenase that catalyses the decarboxylation of 2OG but appears to have different prime substrate requirements from those so far defined for other ALKBH family members. Our findings define a new class of HIF-transcriptional target gene and suggest that ALKBH5 may have a role in the regulation of cellular responses to hypoxia.
Chemistry Research Laboratory and The Oxford Centre for Integrative Systems Biology, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
Armin
A
Thalhammer
Zuzana
Z
Bencokova
Rachel
R
Poole
Christoph
C
Loenarz
Julie
J
Adam
Linda
L
O'Flaherty
Johannes
J
Schödel
David
D
Mole
Konstantinos
K
Giaslakiotis
Christopher J
CJ
Schofield
Ester M
EM
Hammond
Peter J
PJ
Ratcliffe
Patrick J
PJ
Pollard
D000071502:AlkB Homolog 5, RNA Demethylase; D002460:Cell Line; D049308:Dioxygenases; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010105:Oxygenases; D049308:Dioxygenases; C559920:ALKBH5 protein, human; D000071502:AlkB Homolog 5, RNA Demethylase
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