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J. Biol. Chem., Vol. 280, Issue 32, 29374-29380, August 12, 2005

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Identification of TopBP1 as a c-Abl-interacting Protein and a Repressor for c-Abl Expression^*

Li Zeng, Yuanyu Hu, and Baojie Li

From the Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673

Expression of BCR-ABL is the leading cause of chronic myelogenous leukemia. In chronic myelogenous leukemia cells, c-Abl expression is silenced by promoter methylation. In addition, the level of c-Abl needs to be tightly and constantly regulated due to its cytotoxicity and its rapid degradation after activation. Yet the regulation of c-Abl expression remains unclear. In an effort to gain better understanding of c-Abl function, we performed a glutathione S-transferase-Abl pull-down screen and identified TopBP1, a topoisomerase II-binding protein that contains Brca1 C-terminal motifs and has been implicated in DNA damage response. Their physical interaction was verified by in vitro and in vivo assays with TopBP1 found as a substrate of Abl proteins. TopBP1 could repress the expression of c-Abl at both mRNA and protein levels. Reporter assays indicate that TopBP1 directly repressed the promoter activity of c-Abl. Furthermore, TopBP1 repressed expression of c-Abl through a novel mechanism that involved histone deacetylation and DNA methylation. This transcriptional repression was inhibited by c-Abl in a kinase-dependent manner. The dual antagonistic interplay between c-Abl and TopBP1 may also provide a mechanism for fine-tuning of c-Abl levels.

Received for publication, March 18, 2005 , and in revised form, May 25, 2005.

^* This work is supported by the Agency for Science, Technology, and Research of Singapore. 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.

Adjunct staff members of the Dept. of Medicine of the National University of Singapore.

To whom correspondence should be addressed. Tel.: 65-6586-9679; Fax: 65-6779-1117; E-mail: libj{at}imcb.a-star.edu.sg.

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