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p53 is regulated by the lysine demethylase LSD1

Abstract

p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation1,2. Histone lysine methylation has recently been shown to be reversible; however, it is not known whether non-histone proteins are substrates for demethylation. Here we show that, in human cells, the histone lysine-specific demethylase LSD1 (refs 3, 4) interacts with p53 to repress p53-mediated transcriptional activation and to inhibit the role of p53 in promoting apoptosis. We find that, in vitro, LSD1 removes both monomethylation (K370me1) and dimethylation (K370me2) at K370, a previously identified Smyd2-dependent monomethylation site2. However, in vivo, LSD1 shows a strong preference to reverse K370me2, which is performed by a distinct, but unknown, methyltransferase. Our results indicate that K370me2 has a different role in regulating p53 from that of K370me1: K370me1 represses p53 function, whereas K370me2 promotes association with the coactivator 53BP1 (p53-binding protein 1) through tandem Tudor domains in 53BP1. Further, LSD1 represses p53 function through the inhibition of interaction of p53 with 53BP1. These observations show that p53 is dynamically regulated by lysine methylation and demethylation and that the methylation status at a single lysine residue confers distinct regulatory output. Lysine methylation therefore provides similar regulatory complexity for non-histone proteins and for histones.

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Figure 1: LSD1 interacts with p53.
Figure 2: LSD1 represses the activity of p53.
Figure 3: LSD1 demethylates p53 at K370.
Figure 4: LSD1 represses the activity of p53 through 53BP1.

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References

  1. Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004)

    Article  ADS  CAS  Google Scholar 

  2. Huang, J. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006)

    Article  ADS  CAS  Google Scholar 

  3. Hakimi, M. A., Dong, Y., Lane, W. S., Speicher, D. W. & Shiekhattar, R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J. Biol. Chem. 278, 7234–7239 (2003)

    Article  CAS  Google Scholar 

  4. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004)

    Article  CAS  Google Scholar 

  5. Lee, M. G., Wynder, C., Cooch, N. & Shiekhattar, R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005)

    Article  ADS  CAS  Google Scholar 

  6. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005)

    Article  ADS  CAS  Google Scholar 

  7. Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279–282 (1998)

    Article  CAS  Google Scholar 

  8. Shaulian, E., Zauberman, A., Ginsberg, D. & Oren, M. Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol. Cell. Biol. 12, 5581–5592 (1992)

    Article  CAS  Google Scholar 

  9. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006)

    Article  ADS  CAS  Google Scholar 

  10. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006)

    Article  CAS  Google Scholar 

  11. Barlev, N. A. et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol. Cell 8, 1243–1254 (2001)

    Article  CAS  Google Scholar 

  12. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997)

    Article  CAS  Google Scholar 

  13. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872 (2005)

    Article  CAS  Google Scholar 

  14. Wysocka, J. et al. A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling. Nature 442, 86–90 (2006)

    Article  ADS  CAS  Google Scholar 

  15. Shi, X. et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature 442, 96–99 (2006)

    Article  ADS  CAS  Google Scholar 

  16. Pena, P. V. et al. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature 442, 100–103 (2006)

    Article  ADS  CAS  Google Scholar 

  17. Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006)

    Article  ADS  CAS  Google Scholar 

  18. Kim, J. et al. Tudor, MBT and chromo domains gauge the degree of lysine methylation. EMBO Rep. 7, 397–403 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004)

    Article  ADS  CAS  Google Scholar 

  20. Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4–K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006)

    Article  CAS  Google Scholar 

  21. Iwabuchi, K., Bartel, P. L., Li, B., Marraccino, R. & Fields, S. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl Acad. Sci. USA 91, 6098–6102 (1994)

    Article  ADS  CAS  Google Scholar 

  22. Sengupta, S. et al. Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. J. Cell Biol. 166, 801–813 (2004)

    Article  CAS  Google Scholar 

  23. Ward, I. et al. The tandem BRCT domain of 53BP1 is not required for its repair function. J. Biol. Chem. 281, 38472–38477 (2006)

    Article  CAS  Google Scholar 

  24. Iwabuchi, K. et al. Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2. J. Biol. Chem. 273, 26061–26068 (1998)

    Article  CAS  Google Scholar 

  25. Brummelkamp, T. R. et al. An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nature Chem. Biol. 2, 202–206 (2006)

    Article  CAS  Google Scholar 

  26. Toledo, F. & Wahl, G. M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Rev. Cancer 6, 909–923 (2006)

    Article  CAS  Google Scholar 

  27. Morales, J. C. et al. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proc. Natl Acad. Sci. USA 103, 3310–3315 (2006)

    Article  ADS  CAS  Google Scholar 

  28. Forneris, F., Binda, C., Vanoni, M. A., Battaglioli, E. & Mattevi, A. Human histone demethylase LSD1 reads the histone code. J. Biol. Chem. 280, 41360–41365 (2005)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank N. Barlev for the Set9 expression vector; D. Reinberg for the p53K372me1 antibody; S. Benchimol for the BJ and BJ-DNp53 cell lines; T. Halazonetis for 53BP1 plasmid; R. Schule for p21 luciferase vector; and members of the T.J. and S.L.B. laboratories for discussions. This project is funded, in part, by a AACR-Pennsylvania Department of Health Fellows grant and Leukemia and Lymphoma Society Special Fellow grant (J.H.). M.T.B. is supported by a Welch Foundation grant. Research in the laboratory of T.J. is supported by the IMP through Boehringer Ingelheim and by grants from the European Union and the Austrian GEN-AU initiative, which is financed by the Austrian Ministry of Education, Science and Culture. Research support to S.L.B. was provided by a grant from the National Cancer Institute at NIH and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.

Author Contributions J.H., R.S., A.B.E., M.G.L., J.A.D., M.R. and S.O. performed the experimental work; R.S., M.T.B., T.J. and S.L.B. were responsible for project planning and data analysis.

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Correspondence to Shelley L. Berger.

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Huang, J., Sengupta, R., Espejo, A. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007). https://doi.org/10.1038/nature06092

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