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Office of Biological and Environmental Research

DOE Lowdose Radiation Program Workshop V

Abstract

Title: DNA Damage Response and Ku80 Function in the Vertebrate Embryo

Authors: Catherine L. Bladen, Wai K. Lam, William S. Dynan, and David J. Kozlowski

Institutions: Institute of Molecular Medicine and Genetics, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, 30912, USA Corresponding author: IMMAG, CB-2803, Medical College of Georgia,1120 15th Street, Augusta, GA 30912. Phone: (706) 721-8760. Fax: (706) 721-8752. E-mail: dkozlowski@mcg.edu

Cellular responses to DNA damage reflect the dynamic integration of cell cycle control, cell-cell interactions, and tissue-specific patterns of gene regulation that occur in vivo but are not recapitulated in cell culture models. Here we describe use of the zebrafish embryo as a model system to identify determinants of the in vivo response to ionizing radiation-induced DNA damage. To demonstrate the utility of the model we cloned and characterized the embryonic function of the XRCC5 gene, which encodes Ku80, an essential component of the nonhomologous end-joining pathway of DNA repair. After the onset of zygotic transcription, Ku80 mRNA accumulates in a tissue-specific pattern, which includes proliferative zones of the retina and central nervous system. In the absence of genotoxic stress, zebrafish embryos with reduced Ku80 function develop normally. However, low-dose irradiation of these embryos during gastrulation leads to marked apoptosis throughout the developing central nervous system. Apoptosis is p53 dependent, indicating that it is a downstream consequence of unrepaired DNA damage. Results suggest that nonhomologous end joining components mediate DNA repair to promote survival of irradiated cells during embryogenesis.