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J. Biol. Chem., Vol. 282, Issue 50, 36177-36189, December 14, 2007

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Role for KAP1 Serine 824 Phosphorylation and Sumoylation/Desumoylation Switch in Regulating KAP1-mediated Transcriptional Repression^*

Xu Li¹, Yung-Kang Lee¹, Jen-Chong Jeng^¶, Yun Yen, David C. Schultz^||, Hsiu-Ming Shih^¶, and David K. Ann²

From the Department of Molecular and Clinical Pharmacology, City of Hope, Duarte, California 91010, Department of Pharmacology and Pharmaceutical Science, University of Southern California, Los Angeles, California, 90033, ^¶Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China, and ^||The Wistar Institute, Philadelphia, Pennsylvania 19104

As a multifunctional protein, KRAB domain-associated protein 1 (KAP1) is reportedly subjected to multiple protein posttranslational modifications, including phosphorylation and sumoylation. However, gaps exist in our knowledge of how KAP1 phosphorylation cross-talks with KAP1 sumoylation and what the biological consequence is. Here, we show that doxorubicin (Dox) treatment induces KAP1 phosphorylation at Ser-824 via an ataxia telangiectasia mutated (ATM)-dependent manner, correlating with the transcriptional de-repression of p21^WAF1/CIP1 and Gadd45. A S824A substitution of KAP1, which ablates the ATM-induced phosphorylation, results in an increase of KAP1 sumoylation and repression of p21 transcription in Dox-treated cells. By contrast, a S824D mutation of KAP1, which mimics constitutive phosphorylation of KAP1, leads to a decrease of KAP1 sumoylation and stimulation of p21 transcription before the exposure of Dox. We further provide evidence that SENP1 deSUMOylase is involved in activating basal, but not Dox-induced, KAP1 Ser-824 phosphorylation, rendering a stimulation of p21 and Gadd45 transcription. Moreover, KAP1 and differential sumoylation of KAP1 were also demonstrated to fine-tune the transcription of three additional KAP1-targeted genes, including Bax, Puma, and Noxa. Taken together, our results suggest a novel role for ATM that selectively stimulates KAP1 Ser-824 phosphorylation to repress its sumoylation, leading to the de-repression of expression of a subset of genes involved in promoting cell cycle control and apoptosis in response to genotoxic stresses.

Received for publication, August 20, 2007 , and in revised form, October 9, 2007.

^* This work was supported in part by National Institute of Health Research Grants R01 DE 10742 and DE 14183 (to D. K. A.) and Taiwan National Health Research Institutes Grant MG-092-PP-03 (to H. M.-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.

¹ Both authors contributed equally.

² To whom correspondence should be addressed: City of Hope, Dept. of Clinical and Molecular Pharmacology, 1500 East Duarte Rd., Duarte, CA 91010. Tel.: 626-256-4673 (ext. 64442 or 65707); Fax: 626-471-7204; E-mail: dann{at}coh.org.

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