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

doi:10.1016/S0092-8674(02)00972-8

Bcl-x_L 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 journal › Article › peer-review

205 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-x_L, and we demonstrate that deamidation of these asparagines imports susceptibility to apoptosis by disrupting the ability of Bcl-x_L to block the proapoptotic activity of BH3 domain-only proteins. Conversely, Bcl-x_L 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-x_L deamidation has a critical role in the tumor-specific activity of DNA-damaging antineoplastic agents.

Original language	English (US)
Pages (from-to)	51-62
Number of pages	12
Journal	Cell
Volume	111
Issue number	1
DOIs	https://doi.org/10.1016/S0092-8674(02)00972-8
State	Published - Oct 4 2002
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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@article{4e6904dc6dfa469c889343ceb20887d0,

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

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.",

author = "Deverman, {Benjamin E.} and Cook, {Brian L.} and Manson, {Scott R.} and Niederhoff, {Robert A.} and Langer, {Ellen M.} and Ivana Rosov{\'a} and Kulans, {Laura A.} and Xiaoyun Fu and Weinberg, {Justin S.} and Heinecke, {Jay W.} and Roth, {Kevin A.} and Weintraub, {Steven J.}",

note = "Funding Information: We thank N. Dean, E. Johnson, B. Klocke, E. Knudsen, and G. Putcha for advice and reagents. E.M.L. is a Howard Hughes Medical Institute Predoctoral Fellow. This work was supported by grants from the NIH and the Siteman Cancer Center.",

year = "2002",

month = oct,

day = "4",

doi = "10.1016/S0092-8674(02)00972-8",

language = "English (US)",

volume = "111",

pages = "51--62",

journal = "Cell",

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publisher = "Cell Press",

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TY - JOUR

T1 - Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage

AU - Deverman, Benjamin E.

AU - Cook, Brian L.

AU - Manson, Scott R.

AU - Niederhoff, Robert A.

AU - Langer, Ellen M.

AU - Rosová, Ivana

AU - Kulans, Laura A.

AU - Fu, Xiaoyun

AU - Weinberg, Justin S.

AU - Heinecke, Jay W.

AU - Roth, Kevin A.

AU - Weintraub, Steven J.

N1 - Funding Information: We thank N. Dean, E. Johnson, B. Klocke, E. Knudsen, and G. Putcha for advice and reagents. E.M.L. is a Howard Hughes Medical Institute Predoctoral Fellow. This work was supported by grants from the NIH and the Siteman Cancer Center.

PY - 2002/10/4

Y1 - 2002/10/4

N2 - 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.

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

Abstract

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