Cell Biology

Bcl2 Blocks DNA Repair

Science Signaling  15 Apr 2008:
Vol. 1, Issue 15, pp. ec134
DOI: 10.1126/stke.115ec134

Bcl2 is an oncogenic protein best known for its role as an inhibitor of apoptosis through its actions at the mitochondria. However, Bcl2 was initially identified as associated with a chromosomal breakpoint, not as a mitochondrial protein, which suggests that it has additional functions beyond those at the mitochondria. Zhao et al. report that a nuclear function of Bcl2 appears to be inhibition of the DNA repair enzyme APE1, which mediates the repair of apurinic/apyrimidinic (also known as abasic) sites that occur thousands of times each day in a cell due to various environmental stresses. Abasic sites are produced by the carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is found in cigarette smoke. First the authors compared the abasic site repair activity in human lung cancer cell lines and found that there was an inverse correlation between the repair activity and the abundance of Bcl2. When Bcl2 was overexpressed in cells in which endogenous Bcl2 was undetectable, APE1 activity was reduced. Furthermore, in the Bcl2-overexpressing cells, abasic sites induced by NNK were more abundant than in cells transfected with vector alone. Cell lines in which endogenous Bcl2 was abundant exhibited nuclear accumulation, without loss of Bcl2 from the mitochondria, in response to exposure to NNK, and in NNK-treated cells Bcl2 and APE1 coimmunoprecipitated. The interaction between Bcl2 and APE1 and the ability of Bcl2 to inhibit APE1 activity in vitro and abasic site repair in cultured cells required all four BH3 domains of Bcl2. Finally, the endonuclease activity of APE1 is enhanced by interaction with XRCC1, and this interaction was diminished in cells overexpressing Bcl2, and the APE1-XRCC1 complex was dissociated in vitro when purified Bcl2 was added. Thus, inhibition of DNA repair may contribute to the oncogenic properties of Bcl2.

J. Zhao, F. Gao, Y. Zhang, K. Wei, Y. Liu, X. Deng, Bcl2 inhibits abasic site repair by down-regulating APE1 endonuclease activity. J. Biol. Chem. 283, 9925-9932 (2008). [Abstract] [Full Text]