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Arkady Celeste,1Simone Petersen,1Peter J. Romanienko,2Oscar Fernandez-Capetillo,1Hua Tang Chen,1Olga A. Sedelnikova,3Bernardo Reina-San-Martin,4Vincenzo Coppola,5Eric Meffre,4Michael J. Difilippantonio,6Christophe Redon,3Duane R. Pilch,3Alexandru Olaru,7Michael Eckhaus,8R. Daniel Camerini-Otero,2Lino Tessarollo,5Ferenc Livak,7Katia Manova,9William M. Bonner,3Michel C. Nussenzweig,4André 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
withthe recruitment of repair factors to damaged DNA. To help clarifythe physiological role of H2AX, we targeted H2AX in mice. AlthoughH2AX
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 phenotypeswere 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
facilitatingthe 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}nih.gov
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