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Targeted Deletion of Rad9 in Mouse Skin Keratinocytes Enhances Genotoxin-Induced Tumor Development

¹ National Laboratory of Biomacromolecules, and ² Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, ³ College of Life Science, Capital Normal University, and ⁴ Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China; and ⁵ Center for Radiological Research, College of Physicians and Surgeons and ⁶ Department of Environmental Health Sciences, Columbia University, Mailman School of Public Health, New York, New York

Requests for reprints: Haiying Hang, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China. Phone/Fax: 86-010-6488-8473; E-mail: hh91{at}sun5.ibp.ac.cn or Xiao Yang, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China. Phone/Fax: 86-10-63895937; E-mail: yangx{at}nic.bmi.ac.cn or Howard B. Lieberman, Center for Radiological Research, Columbia University, 630 West 168th St., New York, NY 10032. Phone: 212-305-9241; Fax: 212-342-5505; E-mail: lieberman{at}cancercenter.columbia.edu.

Key Words: Rad9 • conditional gene knockout • genomic stability • skin tumorigenesis • skin aging

The Rad9 gene is evolutionarily conserved from yeast to humans and plays crucial roles in genomic maintenance, DNA repair, and cell cycle checkpoint controls. However, the function of this gene with respect to tumorigenesis is not well-understood. A Rad9-null mutation in mice causes embryonic lethality. In this study, we created mice in which mouse Rad9, Mrad9, was deleted only in keratinocytes to permit examination of the potential function of the gene in tumor development. Mice with Mrad9^+/– or Mrad9^–/– keratinocytes showed no overt, spontaneous morphologic defects and seemed similar to wild-type controls. Painting the carcinogen 7,12-dimethylbenzanthracene (DMBA) onto the skin of the animals caused earlier onset and more frequent formation of tumors and senile skin plaques in Mrad9^–/– mice, compared with Mrad9^+/– and Mrad9^+/+ littermates. DNA damage response genes p21, p53, and Mrad9B were expressed at higher levels in Mrad9^–/– relative to Mrad9^+/+ skin. Keratinocytes isolated from Mrad9^–/– skin had more spontaneous and DMBA-induced DNA double strand breaks than Mrad9^+/+ keratinocytes, and the levels were reduced by incubation with the antioxidant epigallocatechin gallate. These data suggest that Mrad9 plays an important role in maintaining genomic stability and preventing tumor development in keratinocytes. [Cancer Res 2008;68(14):5552–61]