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Molecular and Cellular Biology, January 2008, p. 435-447, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00607-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transcriptional Activation of Histone Genes Requires NPAT-Dependent Recruitment of TRRAP-Tip60 Complex to Histone Promoters during the G₁/S Phase Transition ^,

Michael DeRan,^1,2, Mary Pulvino,^1, Eriko Greene,^1, Chuan Su,^1,¶ and Jiyong Zhao^1*

Department of Biomedical Genetics,¹ Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester New York 14642²

Received 6 April 2007/ Returned for modification 15 June 2007/ Accepted 11 October 2007

Transcriptional activation of histone subtypes is coordinately regulated and tightly coupled with the onset of DNA replication during S-phase entry. The underlying molecular mechanisms for such coordination and coupling are not well understood. The cyclin E-Cdk2 substrate NPAT has been shown to play an essential role in the transcriptional activation of histone genes at the G₁/S-phase transition. Here, we show that NPAT interacts with components of the Tip60 histone acetyltransferase complex through a novel amino acid motif, which is functionally conserved in E2F and adenovirus E1A proteins. In addition, we demonstrate that transformation/transactivation domain-associated protein (TRRAP) and Tip60, two components of the Tip60 complex, associate with histone gene promoters at the G₁/S-phase boundary in an NPAT-dependent manner. In correlation with the association of the TRRAP-Tip60 complex, histone H4 acetylation at histone gene promoters increases at the G₁/S-phase transition, and this increase involves NPAT function. Suppression of TRRAP or Tip60 expression by RNA interference inhibits histone gene activation. Thus, our data support a model in which NPAT recruits the TRRAP-Tip60 complex to histone gene promoters to coordinate the transcriptional activation of multiple histone genes during the G₁/S-phase transition.

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* Corresponding author. Mailing address: Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642. Phone: (585) 273-1453. Fax: (585) 273-1450. E-mail: Jiyong_zhao{at}urmc.rochester.edu

Published ahead of print on 29 October 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to this work.

Present address: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231.

^¶ Present address: Department of Parasitology, Nanjing Medical University, Nanjing, Jiangsu 210029, People's Republic of China.

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Molecular and Cellular Biology, January 2008, p. 435-447, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00607-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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