Methylation-mediated regulation of E2F1 in DNA damage-induced cell death

Abstract

E2F1 promotes DNA damage-induced apoptosis and the post-translational modifications of E2F1 play an important role in the regulation of E2F1-mediated cell death. Here, we found that Set9 and LSD1 regulate E2F1-mediated apoptosis upon DNA damage. Set9 methylates E2F1 at lysine 185, a conserved residue in the DNA-binding domain of E2F family proteins. The methylation of E2F1 by Set9 leads to the stabilization of E2F1 and up-regulation of its proapoptotic target genes p73 and Bim, and thereby induces E2F1-mediated apoptosis in response to genotoxic agents. We also found that LSD1 demethylates E2F1 at lysine 185 and reduces E2F1-mediated cell death. The identification of the methylation/demethylation of E2F1 by Set9/LSD1 suggests that E2F1 is dynamically regulated by epigenetic enzymes in response to DNA damage.

Keywords::

• Methylation
• signal transduction
• apoptosis

Acknowledgements

We thank Dr. Qiang Yu (Genome Institute of Singapore, Singapore) for the Bim-Luc, Dr. J. Ren for the HCT116 p53^−/− cells, and members of the Yuan laboratory for discussion and critical reading of the manuscript. This work is supported by National Science Foundation of China (30870792, 81030025), and Ministry of Science and Technology of China (973-2009CB918704) and Special Funds of State Key Laboratories (2060204).

Declaration of interest

All the authors claim no conflict of interest.