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Author Notes:

To whom correspondence should be addressed. Tel: +1 706 721 8760; Fax: +1 706 721 8752; Email: dkozlowski@mcg.edu

We thank Dr B. Yuan and the MCG Transgenic Zebrafish Core Facility for embryo production, Dr L. McCluskey for cryotome use, Mr Sammy Navarre for advice and support, Drs J. Hardin and S. Lin for stimulating initial interest in the zebrafish as a radiobiological model, Dr P. Chang (University of Singapore) for providing an independent clone of zebrafish Ku80, and members of our laboratories for critical reading of the manuscript.

Conflict of interest statement. None declared.

Subjects:

Research Funding:

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:

  • Amino Acid Sequence
  • Animals
  • Antigens, Nuclear
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • Embryo, Nonmammalian
  • Ku Autoantigen
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • RNA, Messenger
  • Radiation Tolerance
  • Radiation, Ionizing
  • Zebrafish
  • Zebrafish Proteins

DNA damage response and Ku80 function in the vertebrate embryo

Tools:

Journal Title:

Nucleic Acids Research

Volume:

Volume 33, Number 9

Publisher:

, Pages 3002-3010

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author 2005. Published by Oxford University Press. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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