The JmjC domain histone demethylase Ndy1 regulates redox homeostasis and protects cells from oxidative stress.
The histone H3 demethylase Ndy1/KDM2B protects cells from replicative senescence. Changes in the metabolism of reactive oxygen species (ROS) are important for establishing senescence, suggesting that Ndy1 may play a role in redox regulation. Here we show that Ndy1 protects from H(2)O(2)-induced apoptosis and G(2)/M arrest and inhibits ROS-mediated signaling and DNA damage, while knockdown of Ndy1 has the opposite effects. Consistent with these observations, whereas Ndy1 overexpression promotes H(2)O(2) detoxification, Ndy1 knockdown inhibits it. Ndy1 promotes the expression of genes encoding the antioxidant enzymes aminoadipic semialdehyde synthase (Aass), NAD(P)H quinone oxidoreductase-1 (Nqo1), peroxiredoxin-4 (Prdx4), and serine peptidase inhibitor b1b (Serpinb1b) and represses the expression of interleukin-19. At least two of these genes (Nqo1 and Prdx4) are regulated directly by Ndy1, which binds to specific sites within their promoters and demethylates promoter-associated histone H3 dimethylated at K36 and histone H3 trimethylated at K4. Simultaneous knockdown of Aass, Nqo1, Prdx4, and Serpinb1b in Ndy1-expressing cells to levels equivalent to those detected in control cells was sufficient to suppress the Ndy1 redox phenotype.
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Christos
C
Polytarchou
Raymond
R
Pfau
Maria
M
Hatziapostolou
Philip N
PN
Tsichlis
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage; D003849:Deoxyguanosine / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D006706:Homeostasis; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D000975:Antioxidants; D044783:F-Box Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C534140:Ndy1 protein, mouse; D010089:Oxidoreductases, N-Demethylating; D003849:Deoxyguanosine