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Molecular and Cellular Biology, December 2008, p. 7451-7464, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00688-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress {triangledown} ,{dagger}

Christos Polytarchou, Raymond Pfau, Maria Hatziapostolou, and Philip N. Tsichlis*

Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111

Received 28 April 2008/ Returned for modification 23 July 2008/ Accepted 29 September 2008

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 H2O2-induced apoptosis and G2/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 H2O2 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.

* Corresponding author. Mailing address: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111. Phone: (617) 636-6111. Fax: (671) 636-6127. E-mail: ptsichlis{at}tuftsmedicalcenter.org

{triangledown} Published ahead of print on 6 October 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2008, p. 7451-7464, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00688-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tzatsos, A., Pfau, R., Kampranis, S. C., Tsichlis, P. N. (2009). Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc. Natl. Acad. Sci. USA 106: 2641-2646 [Abstract] [Full Text]  


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