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Hbo1 Links p53-Dependent Stress Signaling to DNA Replication Licensing

Masayoshi Iizuka,^1,2 Olga F. Sarmento,¹ Takao Sekiya,^3, Heidi Scrable,⁴ C. David Allis,^2, and M. Mitchell Smith^1*

Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908,¹ Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia 22908,² Oncogene Division, National Cancer Center Research Institute, Tsukiji, Tokyo 104-0045, Japan,³ Department of Neuroscience, University of Virginia Health System, Charlottesville, Virginia 22908⁴

Received 16 April 2007/ Returned for modification 16 May 2007/ Accepted 4 October 2007

Hbo1 is a histone acetyltransferase (HAT) that is required for global histone H4 acetylation, steroid-dependent transcription, and chromatin loading of MCM2-7 during DNA replication licensing. It is the catalytic subunit of protein complexes that include ING and JADE proteins, growth regulatory factors and candidate tumor suppressors. These complexes are thought to act via tumor suppressor p53, but the molecular mechanisms and links between stress signaling and chromatin, are currently unknown. Here, we show that p53 physically interacts with Hbo1 and negatively regulates its HAT activity in vitro and in cells. Two physiological stresses that stabilize p53, hyperosmotic shock and DNA replication fork arrest, also inhibit Hbo1 HAT activity in a p53-dependent manner. Hyperosmotic stress during G₁ phase specifically inhibits the loading of the MCM2-7 complex, providing an example of the chromatin output of this pathway. These results reveal a direct regulatory connection between p53-responsive stress signaling and Hbo1-dependent chromatin pathways.

Published ahead of print on 22 October 2007.

Present address: Mitsubishi Kagaku Institute of Life Sciences, Machida, Tokyo 194-8511, Japan.

Present address: Laboratory of Chromatin Biology, Rockefeller University, New York, NY 10021.