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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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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