Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage.
Deverman BE, Cook BL, Manson SR, Niederhoff RA, Langer EM, Rosová I, Kulans LA, Fu X, Weinberg JS, Heinecke JW, Roth KA, Weintraub SJ
Cell (2002)
Category: apoptosis ¤ Added: Mar 19, 2004 ¤ Rating: ◊
The therapeutic value of DNA-damaging antineoplastic agents is dependent upon their ability to induce tumor cell apoptosis while sparing most normal tissues. Here, we show that a component of the apoptotic response to these agents in several different types of tumor cells is the deamidation of two asparagines in the unstructured loop of Bcl-xL, and we demonstrate that deamidation of these asparagines imports susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3 domain-only proteins. Conversely, Bcl-xL deamidation is actively suppressed in fibroblasts, and suppression of deamidation is an essential component of their resistance to DNA damage-induced apoptosis. Our results suggest that the regulation of Bcl-xL deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents.
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