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J. Biol. Chem., Vol. 279, Issue 44, 45810-45814, October 29, 2004

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Histone H2AX Is Phosphorylated at Sites of Retroviral DNA Integration but Is Dispensable for Postintegration Repair^*

René Daniel¶, Joseph Ramcharan, Emmy Rogakou||**, Konstantin D. Taganov, James G. Greger, William Bonner||, André Nussenzweig, Richard A. Katz, and Anna Marie Skalka¶¶

From the Fox Chase Cancer Center, Institute for Cancer Research, Philadelphia, Pennsylvania 19111-2497, ^||Laboratory of Molecular Pharmacology, NCI, National Institutes of Health, Bethesda, Maryland 20892, and Experimental Immunology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892

The histone variant H2AX is rapidly phosphorylated (denoted H2AX) in large chromatin domains (foci) flanking double strand DNA (dsDNA) breaks that are produced by ionizing radiation or genotoxic agents and during V(D)J recombination. H2AX-deficient cells and mice demonstrate increased sensitivity to dsDNA break damage, indicating an active role for H2AX in DNA repair; however, H2AX formation is not required for V(D)J recombination. The latter finding has suggested a greater dependence on H2AX for anchoring free broken ends versus ends that are held together during programmed breakage-joining reactions. Retroviral DNA integration produces a unique intermediate in which a dsDNA break in host DNA is held together by the intervening viral DNA, and such a reaction provides a useful model to distinguish H2AX functions. We found that integration promotes transient formation of H2AX at retroviral integration sites as detected by both immunocytological and chromatin immunoprecipitation methods. These results provide the first direct evidence for the association of newly integrated viral DNA with a protein species that is an established marker for the onset of a DNA damage response. We also show that H2AX is not required for repair of the retroviral integration intermediate as determined by stable transduction. These observations provide independent support for an anchoring model for the function of H2AX in chromatin repair.

Received for publication, July 13, 2004 , and in revised form, August 10, 2004.

^* This work was supported by National Institutes of Health Grants AI40385, CA71515, CA98090, and CA06927, a Tobacco Formula Research Fund Grant from the Pennsylvania Department of Health, and by an appropriation from the Commonwealth of Pennsylvania. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Present address: Thomas Jefferson University, 1020 Walnut St., Philadelphia, PA 19107-5587.

^** Present address: Inst. of Molecular Biology and Genetics, Biomedical Sciences Research Center "Al. Fleming," 34 Al. Fleming St., Vari-Athens 16602, Greece.

Present address: California Institute of Technology, Pasadena, CA 91125.

^¶¶ To whom correspondence should be addressed: Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111-2497. Tel: 215-728-2490; Fax: 215-728-2778; E-mail: AM_skalka{at}fccc.edu.

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