p53 is regulated by the lysine demethylase LSD1

Jing Huang, Roopsha Sengupta, Alexsandra B. Espejo, Min Gyu Lee, Jean A. Dorsey, Mario Richter, Susanne Opravil, Ramin Shiekhattar, Mark T. Bedford, Thomas Jenuwein, Shelley L. Berger

Research output: Contribution to journalArticle

458 Citations (Scopus)

Abstract

p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. 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 site. 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.

Original languageEnglish (US)
Pages (from-to)105-108
Number of pages4
JournalNature
Volume449
Issue number7158
DOIs
StatePublished - Sep 6 2007
Externally publishedYes

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Methylation
Lysine
Histones
Histone Demethylases
Methyltransferases
Post Translational Protein Processing
Transcriptional Activation
Carrier Proteins
Proteins
Apoptosis
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Huang, J., Sengupta, R., Espejo, A. B., Lee, M. G., Dorsey, J. A., Richter, M., ... Berger, S. L. (2007). p53 is regulated by the lysine demethylase LSD1. Nature, 449(7158), 105-108. https://doi.org/10.1038/nature06092

p53 is regulated by the lysine demethylase LSD1. / Huang, Jing; Sengupta, Roopsha; Espejo, Alexsandra B.; Lee, Min Gyu; Dorsey, Jean A.; Richter, Mario; Opravil, Susanne; Shiekhattar, Ramin; Bedford, Mark T.; Jenuwein, Thomas; Berger, Shelley L.

In: Nature, Vol. 449, No. 7158, 06.09.2007, p. 105-108.

Research output: Contribution to journalArticle

Huang, J, Sengupta, R, Espejo, AB, Lee, MG, Dorsey, JA, Richter, M, Opravil, S, Shiekhattar, R, Bedford, MT, Jenuwein, T & Berger, SL 2007, 'p53 is regulated by the lysine demethylase LSD1', Nature, vol. 449, no. 7158, pp. 105-108. https://doi.org/10.1038/nature06092
Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M et al. p53 is regulated by the lysine demethylase LSD1. Nature. 2007 Sep 6;449(7158):105-108. https://doi.org/10.1038/nature06092
Huang, Jing ; Sengupta, Roopsha ; Espejo, Alexsandra B. ; Lee, Min Gyu ; Dorsey, Jean A. ; Richter, Mario ; Opravil, Susanne ; Shiekhattar, Ramin ; Bedford, Mark T. ; Jenuwein, Thomas ; Berger, Shelley L. / p53 is regulated by the lysine demethylase LSD1. In: Nature. 2007 ; Vol. 449, No. 7158. pp. 105-108.
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AU - Opravil, Susanne

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AB - p53, the tumour suppressor and transcriptional activator, is regulated by numerous post-translational modifications, including lysine methylation. 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 site. 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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