Bcl2 inhibits abasic site repair by down-regulating APE1 endonuclease activity.
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.
Zhao
Jinfeng
J
Department of Medicine, University of Florida Shands Cancer Center, 1376 Mowry Road, Gainesville, FL 32610-3633, USA.
Gao
Fengqin
F
Zhang
Yangde
Y
Wei
Kun
K
Liu
Yunhai
Y
Deng
Xingming
X
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D000076105:X-ray Repair Cross Complementing Protein 1
D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase