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Molecular and Cellular Biology, October 2007, p. 6756-6769, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00460-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Methylation-Acetylation Interplay Activates p53 in Response to DNA Damage{triangledown}

Gleb S. Ivanov,1,{dagger} Tatyana Ivanova,1,{dagger} Julia Kurash,1,{dagger},{ddagger} Alexey Ivanov,2 Sergey Chuikov,3 Farid Gizatullin,4 Enrique M. Herrera-Medina,1 Frank Rauscher III,2 Danny Reinberg,3 and Nickolai A. Barlev1*

Molecular Oncology Research Institute, NEMC-Tufts, 75 Kneeland St., Boston, Massachusetts 02111,1 The Wistar Institute, 3601 Spruce St., Philadelphia, Pennsylvania 19104,2 HHMI, University of Medicine and Dentistry of New Jersey, 683 Hoes Lane, Piscataway, New Jersey 08854,3 Dana-Farber Cancer Research Institute, 44 Binney Street, Boston, Massachusetts 021154

Received 16 March 2007/ Returned for modification 19 April 2007/ Accepted 13 July 2007

p53, an important tumor suppressor protein, exerts its function mostly as a sequence-specific transcription factor and is subjected to multiple posttranslational modifications in response to genotoxic stress. Recently, we discovered that lysine methylation of p53 at K372 by Set7/9 (also known as SET7 and Set9) is important for transcriptional activation and stabilization of p53. In this report we provide a molecular mechanism for the effect of p53 methylation on transcription. We demonstrate that Set7/9 activity toward p53, but not the nucleosomal histones, is modulated by DNA damage. Significantly, we show that lysine methylation of p53 is important for its subsequent acetylation, resulting in stabilization of the p53 protein. These p53 modification events can be observed on the promoter of p21 gene, a known transcriptional target of p53. Finally, we show that methylation-acetylation interplay in p53 augments acetylation of histone H4 in the promoter of p21 gene, resulting in its subsequent transcriptional activation and, hence, cell cycle arrest. Collectively, these results suggest that the cross talk between lysine methylation and acetylation is critical for p53 activation in response to DNA damage and that Set7/9 may play an important role in tumor suppression.

* Corresponding author. Mailing address: Molecular Oncology Research Institute, NEMC-Tufts, 75 Kneeland St., Boston, MA 02111. Phone: (617) 636-6135. Fax: (617) 636-6127. E-mail: nbarlev{at}tufts-nemc.org

{triangledown} Published ahead of print on 23 July 2007.

{dagger} G.S.I., T.I., and J.K. contributed equally to this study.

{ddagger} Present address: Novartis Institute for Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139.

Molecular and Cellular Biology, October 2007, p. 6756-6769, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00460-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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