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J. Biol. Chem., Vol. 281, Issue 37, 27117-27125, September 15, 2006

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The Involvement of Ataxia-telangiectasia Mutated Protein Activation in Nucleotide Excision Repair-facilitated Cell Survival with Cisplatin Treatment^*

Stephanie L. Colton, Xiaoxin S. Xu, Y. Alan Wang, and Gan Wang¹

From the Institute of Environmental Health Sciences, Karmanos Cancer Research Institute, Wayne State University, Detroit, Michigan 48201

DNA damage can lead to either DNA repair with cell survival or to apoptotic cell death. Although the biochemical processes underlying DNA repair and apoptosis have been extensively studied, the mechanisms by which cells determine whether the damage will be repaired or the apoptotic pathway will be activated is largely unknown. We have studied the role of nucleotide excision repair (NER) in cisplatin DNA damage-induced apoptotic cell death using both normal human fibroblasts and NER-defective xeroderma pigmentosum (XP) XPA and XPG cells. The caspase-3 activation experiment demonstrated a greatly increased casapse-3 activation in the NER-defective cells following cisplatin treatment. The flow cytometry experiment revealed an altered cell cycle arrest pattern of the NER-defective cells following cisplatin treatment. The results obtained from the Western blot experiment showed that NER defects resulted in enhanced CHK1 phosphorylation and p21 induction after cisplatin treatment. The cisplatin treatment-induced ATM phosphorylation, however, was attenuated in NER-defective cells. The results obtained from our immunoprecipitation experiment further demonstrated that the ATM protein interacted with the TFIIH basal transcription factor and the XPG protein of the NER pathway. It also showed that a functional XPC protein was required for the association of the ATM protein to genomic DNA. These results suggest that the NER process may prevent the cisplatin treatment-induced apoptosis by activating the ATM protein, and that the presence of the XPC protein is essential for recruiting the ATM protein to the DNA template.

Received for publication, March 24, 2006 , and in revised form, July 14, 2006.

^* This work was supported by the Microarray and Bioinformatic Facility Core, the Cell Culture Facility Core, the Imaging and Flow Cytometry Facility Core of the Environmental Health Sciences Center in Molecular and Cellular Toxicology with Human Applications Grant P30 ES06639 at Wayne State University, and National Institutes of Health NIEHS, Grant R01ES09699 (to G. W.). 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 Figs. 1 and 2.

¹ To whom all correspondence should be addressed: IEHS, Wayne State University, 2727 Second Ave., Rm. 4000, Detroit, MI 48201. Tel.: 313-964-8140; Fax: 313-577-0082; E-mail: g.wang{at}wayne.edu.

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