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p53-mediated heterochromatin reorganization regulates its cell fate decisions

Nature Structural & Molecular Biology volume 19, pages 478–484 (2012)Cite this article

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Abstract

p53 is a major sensor of cellular stresses, and its activation influences cell fate decisions. We identified SUV39H1, a histone code 'writer' responsible for the histone H3 Lys9 trimethylation (H3K9me3) mark for 'closed' chromatin conformation, as a target of p53 repression. SUV39H1 downregulation was mediated transcriptionally by p21 and post-translationally by MDM2. The H3K9me3 repression mark was found to be associated with promoters of representative p53 target genes and was decreased upon p53 activation. Overexpression of SUV39H1 maintained higher levels of the H3K9me3 mark on these promoters and was associated with decreased p53 promoter occupancy and decreased transcriptional induction in response to p53. Conversely, SUV39H1 pre-silencing decreased H3K9me3 levels on these promoters and enhanced the p53 apoptotic response. These findings uncover a new layer of p53-mediated chromatin regulation through modulation of histone methylation at p53 target promoters.

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Figure 1: p53 downregulates SUV39H1 expression.
Figure 2: Induction of p53 abrogates the H3K9me3 heterochromatin mark.
Figure 3: Overexpression of SUV39H1 inhibits p53-dependent apoptosis.
Figure 4: Silencing of SUV39H1 causes p21-dependent, but p53-independent, cell cycle arrest.
Figure 5: Pre-silencing of SUV39H1 cooperates with chemotherapy-induced apoptosis in a p53-dependent manner.

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Acknowledgements

The authors would like to thank E. Bernstein and her lab members as well as C. Munoz-Fontela, M. Kracikova and W. Murk for helpful discussions. The project was supported by grant P01CA080058 from the National Cancer Institute (to S.A.A. and S.W.L.). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the US National Institutes of Health.

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Authors and Affiliations

  1. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Sathish Kumar Mungamuri, Erica Kay Benson & Stuart A Aaronson

  2. University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA

    Shaomeng Wang

  3. Department of Pathology and Cell Biology, Institute for Cancer Genetics, College of Physicians and Surgeons of Columbia University, New York, New York, USA

    Wei Gu

  4. Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA

    Sam W Lee

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Contributions

S.K.M. and S.A.A. planned the project. S.K.M. conducted all the experiments, with participation by E.K.B. S.W. provided the MI-219 MDM2 inhibitor. S.A.A. supervised the study, along with S.W.L. and W.G. S.K.M. and S.A.A. wrote the paper.

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Correspondence to Stuart A Aaronson.

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Mungamuri, S., Benson, E., Wang, S. et al. p53-mediated heterochromatin reorganization regulates its cell fate decisions. Nat Struct Mol Biol 19, 478–484 (2012). https://doi.org/10.1038/nsmb.2271

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