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Science 296 (5569): 922-927

Copyright © 2002 by the American Association for the Advancement of Science

Genomic Instability in Mice Lacking Histone H2AX

Arkady Celeste,1 Simone Petersen,1 Peter J. Romanienko,2 Oscar Fernandez-Capetillo,1 Hua Tang Chen,1 Olga A. Sedelnikova,3 Bernardo Reina-San-Martin,4 Vincenzo Coppola,5 Eric Meffre,4 Michael J. Difilippantonio,6 Christophe Redon,3 Duane R. Pilch,3 Alexandru Olaru,7 Michael Eckhaus,8 R. Daniel Camerini-Otero,2 Lino Tessarollo,5 Ferenc Livak,7 Katia Manova,9 William M. Bonner,3 Michel C. Nussenzweig,4 André Nussenzweig1*

Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.

1 Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
2 Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
3 Laboratory of Molecular Pharmacology, NIH, Bethesda, MD 20892, USA.
4 Laboratory of Molecular Immunology, The Rockefeller University, Howard Hughes Medical Institute, New York, NY 10021, USA.
5 Mouse Cancer Genetics Program, NIH, Frederick, MD 20892, USA.
6 Genetics Department, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
7 Department of Microbiology and Immunology, University of Maryland School of Medicine, 655 West Baltimore Street, BRB 13-01, Baltimore, MD 21201, USA.
8 Veterinary Resources Program, National Center for Research Resources, NIH, Bethesda, MD 20892, USA.
9 Molecular Cytology Core Facility and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
*   To whom correspondence should be addressed. E-mail: andre_nussenzweig{at}

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ATR and H2AX Cooperate in Maintaining Genome Stability under Replication Stress.
R. A. Chanoux, B. Yin, K. A. Urtishak, A. Asare, C. H. Bassing, and E. J. Brown (2009)
J. Biol. Chem. 284, 5994-6003
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