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Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage

Abstract

The nicotinamide adenine dinucleotide (NAD)-dependent deacetylase Sir2 (silent information regulator 2) regulates gene silencing in yeast and promotes lifespan extension during caloric restriction. The mammalian homologue of Sir2 (SirT1) regulates p53, NF-κB and Forkhead transcription factors, and is implicated in stress response. This report shows that the cell-cycle and apoptosis regulator E2F1 induces SirT1 expression at the transcriptional level. Furthermore, SirT1 binds to E2F1 and inhibits E2F1 activities, forming a negative feedback loop. Knockdown of SirT1 by small interference RNA (siRNA) increases E2F1 transcriptional and apoptotic functions. DNA damage by etoposide causes E2F1-dependent induction of SirT1 expression and knockdown of SirT1 increases sensitivity to etoposide. These results reveal a mutual regulation between E2F1 and SirT1 that affects cellular sensitivity to DNA damage.

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Figure 1: Induction of SirT1 expression by E2F1.
Figure 2: E2F1 induction of SirT1 expression after DNA damage.
Figure 3: Inhibition of E2F1 transcription function by SirT1.
Figure 4: SirT1 inhibits E2F1 apoptotic function.

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References

  1. Guarante, L. P. Regulation of aging by SIR2. Ann. N. Y. Acad. Sci. 1055, 222 (2005).

    Article  Google Scholar 

  2. Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O. & Sinclair, D. A. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423, 181–185 (2003).

    Article  CAS  Google Scholar 

  3. Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).

    Article  CAS  Google Scholar 

  4. Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).

    Article  CAS  Google Scholar 

  5. Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).

    Article  CAS  Google Scholar 

  6. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  Google Scholar 

  7. Langley, E. et al. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 21, 2383–2396 (2002).

    Article  CAS  Google Scholar 

  8. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

    Article  CAS  Google Scholar 

  9. Yang, Y., Hou, H., Haller, E. M., Nicosia, S. V. & Bai, W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 24, 1021–1032 (2005).

    Article  CAS  Google Scholar 

  10. Nahle, Z. et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nature Cell Biol. 4, 859–864 (2002).

    Article  CAS  Google Scholar 

  11. Johnson, D. G., Schwarz, J. K., Cress, W. D. & Nevins, J. R. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365, 349–352 (1993).

    Article  CAS  Google Scholar 

  12. Wu, X. & Levine, A. J. p53 and E2F-1 cooperate to mediate apoptosis. Proc. Natl Acad. Sci. USA 91, 3602–3606 (1994).

    Article  CAS  Google Scholar 

  13. Lin, W. C., Lin, F. T. & Nevins, J. R. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev. 15, 1833–1844 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ma, Y., Yuan, J., Huang, M., Jove, R. & Cress, W. D. Regulation of the cyclin D3 promoter by E2F1. J. Biol. Chem. 278, 16770–16776 (2003).

    Article  CAS  Google Scholar 

  15. Ma, Y., Cress, W. D. & Haura, E. B. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Mol. Cancer Ther. 2, 73–81 (2003).

    CAS  PubMed  Google Scholar 

  16. Nemoto, S., Fergusson, M. M. & Finkel, T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306, 2105–2108 (2004).

    Article  CAS  Google Scholar 

  17. Yeung, F. et al. Modulation of NF-RB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380 (2004).

    Article  CAS  Google Scholar 

  18. Ma, Y., Freeman, S. N. & Cress, W. D. E2F4 deficiency promotes drug-induced apoptosis. Cancer Biol. Ther. 3, 1262–1269 (2004).

    Article  CAS  Google Scholar 

  19. Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998).

    Article  CAS  Google Scholar 

  20. Stevens, C., Smith, L. & La Thangue, N. B. Chk2 activates E2F-1 in response to DNA damage. Nature Cell Biol. 5, 401–409 (2003).

    Article  CAS  Google Scholar 

  21. Johnson, D. G., Ohtani, K. & Nevins, J. R. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev. 8, 1514–1525 (1994).

    Article  CAS  Google Scholar 

  22. Martinez-Balbas, M. A., Bauer, U. M., Nielsen, S. J., Brehm, A. & Kouzarides, T. Regulation of E2F1 activity by acetylation. EMBO J. 19, 662–671 (2000).

    Article  CAS  Google Scholar 

  23. Luo, R. X., Postigo, A. A. & Dean, D. C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473 (1998).

    Article  CAS  Google Scholar 

  24. Kowalik, T. F., DeGregori, J., Leone, G., Jakoi, L. & Nevins, J. R. E2F1-specific induction of apoptosis and p53 accumulation, which is blocked by Mdm2. Cell Growth Differ. 9, 113–118 (1998).

    CAS  PubMed  Google Scholar 

  25. Wang, C. et al. Activation of p27Kip1 Expression by E2F1. A negative feedback mechanism. J. Biol. Chem. 280, 12339–12343 (2005).

    Article  CAS  Google Scholar 

  26. Pruschy, M., Wirbelauer, C., Glanzmann, C., Bodis, S. & Krek, W. E2F-1 has properties of a radiosensitizer and its regulation by cyclin A kinase is required for cell survival of fibrosarcoma cells lacking p53. Cell Growth Differ. 10, 141–146 (1999).

    CAS  PubMed  Google Scholar 

  27. Chen, W. Y. et al. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437–448 (2005).

    Article  CAS  Google Scholar 

  28. Chu, F., Chou, P. M., Zheng, X., Mirkin, B. L. & Rebbaa, A. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res. 65, 10183–10187 (2005).

    Article  CAS  Google Scholar 

  29. Ford, J., Jiang, M. & Milner, J. Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. Cancer Res. 65, 10457–10463 (2005).

    Article  CAS  Google Scholar 

  30. Rogoff, H. A. et al. Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm–Nbs1–Chk2. Mol. Cell Biol. 24, 2968–2977 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank T. Kowalik for the E7 adenovirus, T. Kouzarides for the E2F13R mutant and M. McBurney for SirT1-null MEFs. We also thank the Moffitt Molecular Biology and Flow Cytometry Cores for sequencing and FACS analyses. This work was supported by grants from the National Institutes of Health (NIH) and American Cancer Society (ACS) to J. Chen.

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Correspondence to Jiandong Chen.

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Supplementary Figures S1, S2, S3 and S4 (PDF 4635 kb)

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Wang, C., Chen, L., Hou, X. et al. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 8, 1025–1031 (2006). https://doi.org/10.1038/ncb1468

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