DNA damage response and Ku80 function in the vertebrate embryo

• Type of Material: Article
• Authors: Catherine L. Bladen, Medical College of Georgia; Wai K. Lam, Medical College of Georgia; William Dynan, Emory University; David J. Kozlowski, Medical College of Georgia
• Language: English
• Date: 2005-11-03
• Publisher: Oxford University Press (OUP): Policy C - Option B
• Publication Version: Final Published Version
• Copyright Statement: © The Author 2005. Published by Oxford University Press. All rights reserved.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/nar/gki613
• Title of Journal or Parent Work: Nucleic Acids Research
• ISSN: 0305-1048
• Volume: 33
• Issue: 9
• Start Page: 3002
• End Page: 3010
• Grant/Funding Information: Open Access publication charges and support for this work were provided by grant award DE-FG02-03ER63649 from the U.S. Department of Energy Low Dose Radiation Research Program.
• Keywords: Protein Structure, Tertiary; Radiation Tolerance; DNA Repair; Antigens, Nuclear; DNA Damage; Radiation, Ionizing; Embryo, Nonmammalian; Amino Acid Sequence; Zebrafish; DNA-Binding Proteins; Animals; Ku Autoantigen; Molecular Sequence Data; RNA, Messenger; Zebrafish Proteins
• Research Categories: Biology, Anatomy; Biology, Cell; Biology, Genetics

Abstract

Cellular responses to DNA damage reflect the dynamic integration of cell cycle control, cell-cell interactions and tissue-specific patterns of gene regulation that occurs in vivo but is 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.