Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage

Benjamin E. Deverman, Brian L. Cook, Scott R. Manson, Robert A. Niederhoff, Ellen M. Langer, Ivana Rosová, Laura A. Kulans, Xiaoyun Fu, Justin S. Weinberg, Jay W. Heinecke, Kevin A. Roth, Steven J. Weintraub

Research output: Contribution to journalArticlepeer-review

188 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)51-62
Number of pages12
JournalCell
Volume111
Issue number1
DOIs
StatePublished - Oct 4 2002

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