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J. Biol. Chem., Vol. 283, Issue 5, 2564-2574, February 1, 2008

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An ATM- and Rad3-related (ATR) Signaling Pathway and a Phosphorylation-Acetylation Cascade Are Involved in Activation of p53/p21^Waf1/Cip1 in Response to 5-Aza-2'-deoxycytidine Treatment^*

Haiying Wang, Ying Zhao, Lian Li, Michael A. McNutt, Lipeng Wu, Shaoli Lu, Yu Yu, Wen Zhou, Jingnan Feng, Guolin Chai, Yang Yang, and Wei-Guo Zhu^¶1

From the Departments of Biochemistry and Molecular Biology and Pathology and the ^¶Cancer Research Center, Peking University Health Science Center, Beijing 100083, China

Most agents that damage DNA act through posttranslational modifications of p53 and activate its downstream targets. However, whether cellular responses to nucleoside analogue-induced DNA damage also operate through p53 posttranslational modification has not been reported. In this study, the relationship between p53 activation and its posttranslational modifications was investigated in the human cancer cell lines A549 and HCT116 in response to 5-aza-2'-deoxycytidine (5-aza-CdR) or cytarabine treatment. 5-Aza-CdR induces p53 posttranslational modifications through activation of an ATM- and Rad3-related (ATR) signaling pathway, and 5-aza-CdR-induced association of replication protein A with chromatin is required for the binding of ATR to chromatin. Upon treatment with 5-aza-CdR, ATR activation is clearly associated with p53 phosphorylation at Ser¹⁵, but not at Thr¹⁸, Ser²⁰, or Ser³⁷. This specific p53 phosphorylation at Ser¹⁵ in turn results in acetylation of p53 at Lys³²⁰ and Lys³⁷³/Lys³⁸² through transcriptional cofactors p300/CBP-associated factor and p300, respectively. These p53 posttranslational modifications are directly responsible for 5-aza-CdR induced p21^Waf1/Cip1 expression because the binding activity of acetylated p53 at Lys³²⁰/Lys³⁷³/Lys³⁸² to the p21^Waf1/Cip1 promoter, as well as p21^Waf1/Cip1 expression itself are significantly increased after 5-aza-CdR treatment. It is of interest that p53 phosphorylation at Ser¹⁵ and acetylations at Lys³²⁰/Lys³⁷³/Lys³⁸² mutually interact in the 5-aza-CdR induced p21^Waf1/Cip1 expression shown by transfection of artificially mutated p53 expression vectors including S15A, K320R, and K373R/K382R into p53-null H1299 cells. These data taken together show for the first time that 5-aza-CdR activates the ATR signaling pathway, which elicits a specific p53 phosphorylation-acetylation cascade to induce p21^Waf1/Cip1 expression.

Received for publication, March 22, 2007 , and in revised form, October 30, 2007.

^* This work was supported by National Natural Science Foundation of China Grants 30425017, 30670417, 30700391, and 30621002 and Grants 2005CB522403, 2006AA02Z101, 2006CB910300, and B07001 from the Ministry of Science and Technology of China. 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 To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Peking University Health Science Center, #38 Xueyuan Rd., Beijing 100083, China. Tel./Fax: 86-1082802235; E-mail: zhuweiguo{at}bjmu.edu.cn.

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