Genomic Instability in Mice Lacking Histone H2AX-Reference-Cited by-全球学者库

Genomic Instability in Mice Lacking Histone H2AX

Published:2002-05-03 Issue:5569 Volume:296 Page:922-927
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Celeste Arkady¹,Petersen Simone¹,Romanienko Peter J.²,Fernandez-Capetillo Oscar¹,Chen Hua Tang¹,Sedelnikova Olga A.³,Reina-San-Martin Bernardo⁴,Coppola Vincenzo⁵,Meffre Eric⁴,Difilippantonio Michael J.⁶,Redon Christophe³,Pilch Duane R.³,Olaru Alexandru⁷,Eckhaus Michael⁸,Camerini-Otero R. Daniel²,Tessarollo Lino⁵,Livak Ferenc⁷,Manova Katia⁹,Bonner William M.³,Nussenzweig Michel C.⁴,Nussenzweig André¹

Affiliation:

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.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference35 articles.

1. C. Redon et al. Curr. Opin. Genet. Dev. 12 162 (2002).

2. DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139

3. Megabase Chromatin Domains Involved in DNA Double-Strand Breaks in Vivo

4. H. T. Chen et al. Science 290 1962 (2000).

5. S. Petersen et al. Nature 414 660 (2001).

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