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¹ Department of Radiation Oncology, Diabetes, and Metabolism, Department of Medicine
² Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine
³ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
⁴ Fox Chase Cancer Center, Philadelphia, PA 19111

Address correspondence to Gary D. Kao, Hospital of the University of Pennsylvania, Department of Radiation Oncology, 3400 Spruce St. 2 Donner, Philadelphia, PA 19104. Tel.: (215) 573-5503. Fax: (215) 349-0090. E-mail: kao{at}xrt.upenn.edu

Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage–induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage–induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint.

Key Words: HDAC4; 53BP1; DNA damage; irradiation; G2 checkpoint

^* Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; DNA-PK, DNA protein kinase; HDAC, histone deacetylase; IR, irradiation; NBS, Nijmegen breakage syndrome; RNAi, RNA interference; siRNA, short interfering RNA; TSA, trichostatin A.

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