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J. Biol. Chem., Vol. 282, Issue 40, 29431-29440, October 5, 2007

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Human T-cell Leukemia Virus Type 1 Tax Oncoprotein Prevents DNA Damage-induced Chromatin Egress of Hyperphosphorylated Chk2^*

From the Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia 23507

De novo expression of human T-cell leukemia virus type 1 Tax results in cellular genomic instability. We demonstrated previously that Tax associates with the cell cycle check point regulator Chk2 and proposed that the inappropriate activation of Chk2 provides a model for Tax-induced loss of genetic integrity (Haoudi, A., Daniels, R. C., Wong, E., Kupfer, G., and Semmes, O. J. (2003) J. Biol. Chem. 278, 37736–37744). Here we provide an explanation for how Tax induces some Chk2 activities but represses others. We show that Tax interaction with Chk2 generates two activation signals in Chk2, oligomerization and autophosphorylation. However, egress of Chk2 from chromatin, normally observed in response to ionizing radiation, was repressed in Tax-expressing cells. Analysis of chromatin-bound Chk2 from Tax-expressing cells revealed phosphorylation at Thr³⁷⁸, Ser³⁷⁹, Thr³⁸³, Thr³⁸⁷, and Thr³⁸⁹. In contrast, chromatin-bound Chk2 in the absence of Tax was phosphorylated at Thr³⁸³ and Thr³⁸⁷ in response to ionizing radiation. We further establish that Tax binds to the kinase domain of Chk2. Confocal microscopy revealed a redistribution of Chk2 to colocalize with Tax in Tax speckled structures, which we have shown previously to coincide with interchromatin granules. We propose that Tax binding via the Chk2 kinase domain sequesters phosphorylated Chk2 within chromatin, thus hindering chromatin egress and appropriate response to DNA damage.

Received for publication, May 18, 2007 , and in revised form, July 30, 2007.

^* This work was supported by Department of Health and Human Services Grant CA076595 (to O. J. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Lewis Hall, 700 West Olney Rd., Norfolk, VA 23507. Tel.: 757-446-5676; Fax: 757-446-5766; E-mail: Semmesoj{at}evms.edu.

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