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Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation


DNA methylation is an epigenetic modification that is essential for gene silencing and genome stability in many organisms. Although methyltransferases that promote DNA methylation are well characterized, the molecular mechanism underlying active DNA demethylation is poorly understood and controversial1,2. Here we show that Gadd45a (growth arrest and DNA-damage-inducible protein 45 alpha), a nuclear protein involved in maintenance of genomic stability, DNA repair and suppression of cell growth3,4, has a key role in active DNA demethylation. Gadd45a overexpression activates methylation-silenced reporter plasmids and promotes global DNA demethylation. Gadd45a knockdown silences gene expression and leads to DNA hypermethylation. During active demethylation of oct4 in Xenopus laevis oocytes5, Gadd45a is specifically recruited to the site of demethylation. Active demethylation occurs by DNA repair and Gadd45a interacts with and requires the DNA repair endonuclease XPG. We conclude that Gadd45a relieves epigenetic gene silencing by promoting DNA repair, which erases methylation marks.

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Figure 1: Gadd45a activates methylation-silenced reporter plasmids.
Figure 2: Gadd45a promotes gene-specific and global DNA demethylation.
Figure 3: Gadd45a loss of function induces DNA hypermethylation.
Figure 4: Demethylation by Gadd45a involves DNA repair.


  1. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002)

    Article  CAS  Google Scholar 

  2. Kress, C., Thomassin, H. & Grange, T. Local DNA demethylation in vertebrates: how could it be performed and targeted? FEBS Lett. 494, 135–140 (2001)

    Article  CAS  Google Scholar 

  3. Carrier, F. et al. Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol. Cell. Biol. 19, 1673–1685 (1999)

    Article  CAS  Google Scholar 

  4. Hollander, M. C. & Fornace, A. J. Genomic instability, centrosome amplification, cell cycle checkpoints and Gadd45a. Oncogene 21, 6228–6233 (2002)

    Article  CAS  Google Scholar 

  5. Simonsson, S. & Gurdon, J. DNA demethylation is necessary for the epigenetic reprogramming of somatic cell nuclei. Nature Cell Biol. 6, 984–990 (2004)

    Article  CAS  Google Scholar 

  6. Escher, G. et al. Demethylation using the epigenetic modifier, 5-azacytidine, increases the efficiency of transient transfection of macrophages. J. Lipid Res. 46, 356–365 (2005)

    Article  CAS  Google Scholar 

  7. Shou, W. & Dunphy, W. G. Cell cycle control by Xenopus p28Kix1, a developmentally regulated inhibitor of cyclin-dependent kinases. Mol. Biol. Cell 7, 457–469 (1996)

    Article  CAS  Google Scholar 

  8. Yeom, Y. I. et al. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122, 881–894 (1996)

    CAS  PubMed  Google Scholar 

  9. Hattori, N. et al. Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells. J. Biol. Chem. 279, 17063–17069 (2004)

    Article  CAS  Google Scholar 

  10. Gidekel, S. & Bergman, Y. A unique developmental pattern of Oct-3/4 DNA methylation is controlled by a cis demodification element. J. Biol. Chem. 277, 34521–34530 (2002)

    Article  CAS  Google Scholar 

  11. Furukawa, T. et al. Densely methylated MLH1 promoter correlates with decreased mRNA expression in sporadic colorectal cancers. Genes Chromosom. Cancer 35, 1–10 (2002)

    Article  CAS  Google Scholar 

  12. Li, Q., Ahuja, N., Burger, P. C. & Issa, J. P. Methylation and silencing of the Thrombospondin-1 promoter in human cancer. Oncogene 18, 3284–3289 (1999)

    Article  CAS  Google Scholar 

  13. Fang, J. Y., Lu, J., Chen, Y. X. & Yang, L. Effects of DNA methylation on expression of tumor suppressor genes and proto-oncogenes in human colon cancer cell lines. World J. Gastroenterol. 9, 1976–1980 (2003)

    Article  CAS  Google Scholar 

  14. Jaenisch, R. et al. Nuclear cloning, epigenetic reprogramming, and cellular differentiation. Cold Spring Harb. Symp. Quant. Biol. 69, 19–27 (2004)

    Article  CAS  Google Scholar 

  15. Prives, C. & Foukal, D. Use of oligonucleotides for antisense experiments in Xenopus laevis oocytes. Methods Cell Biol. 36, 185–209 (1991)

    Article  CAS  Google Scholar 

  16. Rhee, I. et al. CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404, 1003–1007 (2000)

    Article  ADS  CAS  Google Scholar 

  17. Smith, M. L. et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266, 1376–1380 (1994)

    Article  ADS  CAS  Google Scholar 

  18. Smith, M. L. et al. Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin. Oncogene 13, 2255–2263 (1996)

    CAS  PubMed  Google Scholar 

  19. Choi, Y. et al. DEMETER, a DNA glycosylase domain protein, is required for endosperm gene imprinting and seed viability in Arabidopsis. Cell 110, 33–42 (2002)

    Article  CAS  Google Scholar 

  20. Jost, J. P. et al. 5-Methylcytosine DNA glycosylase participates in the genome-wide loss of DNA methylation occurring during mouse myoblast differentiation. Nucleic Acids Res. 29, 4452–4461 (2001)

    Article  CAS  Google Scholar 

  21. Gong, Z. et al. ROS1, a repressor of transcriptional gene silencing in Arabidopsis, encodes a DNA glycosylase/lyase. Cell 111, 803–814 (2002)

    Article  CAS  Google Scholar 

  22. Weiss, A., Keshet, I., Razin, A. & Cedar, H. DNA demethylation in vitro: involvement of RNA. Cell 86, 709–718 (1996)

    Article  CAS  Google Scholar 

  23. Reardon, J. T. & Sancar, A. Nucleotide excision repair. Prog. Nucleic Acid Res. Mol. Biol. 79, 183–235 (2005)

    Article  CAS  Google Scholar 

  24. Iyer, N., Reagan, M. S., Wu, K. J., Canagarajah, B. & Friedberg, E. C. Interactions involving the human RNA polymerase II transcription/nucleotide excision repair complex TFIIH, the nucleotide excision repair protein XPG, and Cockayne syndrome group B (CSB) protein. Biochemistry 35, 2157–2167 (1996)

    Article  CAS  Google Scholar 

  25. Yi, Y. W. et al. Gadd45 family proteins are coactivators of nuclear hormone receptors. Biochem. Biophys. Res. Commun. 272, 193–198 (2000)

    Article  CAS  Google Scholar 

  26. Issa, J. P. CpG island methylator phenotype in cancer. Nature Rev. Cancer 4, 988–993 (2004)

    Article  CAS  Google Scholar 

  27. Hansis, C., Barreto, G., Maltry, N. & Niehrs, C. Nuclear reprogramming of human somatic cells by Xenopus egg extract requires BRG1. Curr. Biol. 14, 1475–1480 (2004)

    Article  CAS  Google Scholar 

  28. Davidson, G. et al. Casein kinase 1 γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867–872 (2005)

    Article  ADS  CAS  Google Scholar 

  29. Cimbora, D. M. et al. Long-distance control of origin choice and replication timing in the human β-globin locus are independent of the locus control region. Mol. Cell. Biol. 20, 5581–5591 (2000)

    Article  CAS  Google Scholar 

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We thank L. Sitter for help in characterizing XPG; H. Clevers, N. Giese, H. Schöler, and J. Smith for reagents; and G. Davidson and H. Steinbeisser for helpful discussions. This work was funded by the Deutsche Forschungsgemeinschaft.

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Correspondence to Christof Niehrs.

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This file contains Supplementary Figures S1-S8 with legends, Supplementary Methods with detailed information about the materials and methods used in this report and additional references. (PDF 655 kb)

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Barreto, G., Schäfer, A., Marhold, J. et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445, 671–675 (2007).

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