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J. Biol. Chem. 283 (15): 9925-9932

© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Bcl2 Inhibits Abasic Site Repair by Down-regulating APE1 Endonuclease Activity*

Jinfeng Zhao{ddagger}§, Fengqin Gao{ddagger}§, Yangde Zhang§, Kun Wei, Yunhai Liu§, , and Xingming Deng{ddagger}1

{ddagger}University of Florida Shands Cancer Center, Department of Medicine and Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida 32610-3633, the §National Hepatobiliary and Enteric Surgery Research Center, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China, and the College of Materials Science and Engineering, Guangzhou, Guangdong 510640, China

Abstract: Bcl2 not only prolongs cell survival but also suppresses the repair of abasic (AP) sites of DNA lesions. Apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in the repair of AP sites via the base excision repair pathway. Here we found that Bcl2 down-regulates APE1 endonuclease activity in association with inhibition of AP site repair. Exposure of cells to nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone results in accumulation of Bcl2 in the nucleus and interaction with APE1, which requires all of the BH domains of Bcl2. Deletion of any of the BH domains from Bcl2 abrogates the ability of Bcl2 to interact with APE1 as well as the inhibitory effects of Bcl2 on APE1 activity and AP site repair. Overexpression of Bcl2 in cells reduces formation of the APE1·XRCC1 complex, and purified Bcl2 protein directly disrupts the APE1·XRCC1 complex with suppression of APE1 endonuclease activity in vitro. Importantly, specific knockdown of endogenous Bcl2 by RNA interference enhances APE1 endonuclease activity with accelerated AP site repair. Thus, Bcl2 inhibition of AP site repair may occur in a novel mechanism by down-regulating APE1 endonuclease activity, which may promote genetic instability and tumorigenesis.


Received for publication October 9, 2007. Revision received February 5, 2008.

* This work was supported by NCI, National Institutes of Health Grant R01 CA112183, by a Flight Attendant Medical Research Institute Clinical Innovator Award, and a Fu Rong Scholarship. 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: University of Florida Shands Cancer Center, 1376 Mowry Rd., Cancer/Genetics Research Complex, Rm. 262, Gainesville, FL 32610-3633. Tel.: 352-273-8170; Fax: 352-273-8285; E-mail: xdeng{at}ufl.edu.


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