Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Hong Jen Lee; Li Lan; Guang Peng; Wei Chao Chang; Ming Chuan Hsu; Ying Nai Wang; Chien Chia Cheng; Leizhen Wei; Satoshi Nakajima; Shih Shin Chang; Hsin Wei Liao; Chung Hsuan Chen; Martin Lavin; K. Kian Ang; Shiaw Yih Lin; Mien Chie Hung

doi:10.1038/cr.2015.8

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Hong Jen Lee, Li Lan, Guang Peng, Wei Chao Chang, Ming Chuan Hsu, Ying Nai Wang, Chien Chia Cheng, Leizhen Wei, Satoshi Nakajima, Shih Shin Chang, Hsin Wei Liao, Chung Hsuan Chen, Martin Lavin, K. Kian Ang, Shiaw Yih Lin, Mien Chie Hung

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.

Original language	English (US)
Pages (from-to)	225-236
Number of pages	12
Journal	Cell research
Volume	25
Issue number	2
DOIs	https://doi.org/10.1038/cr.2015.8
State	Published - Feb 5 2015

Keywords

ATM
DNA damage response
EGFR
tyrosine phosphorylation

ASJC Scopus subject areas

Molecular Biology
Cell Biology

MD Anderson CCSG core facilities

Functional Genomics Core

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10.1038/cr.2015.8

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title = "Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response",

abstract = "Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.",

keywords = "ATM, DNA damage response, EGFR, tyrosine phosphorylation",

author = "Lee, {Hong Jen} and Li Lan and Guang Peng and Chang, {Wei Chao} and Hsu, {Ming Chuan} and Wang, {Ying Nai} and Cheng, {Chien Chia} and Leizhen Wei and Satoshi Nakajima and Chang, {Shih Shin} and Liao, {Hsin Wei} and Chen, {Chung Hsuan} and Martin Lavin and Ang, {K. Kian} and Lin, {Shiaw Yih} and Hung, {Mien Chie}",

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year = "2015",

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AU - Lee, Hong Jen

AU - Lan, Li

AU - Peng, Guang

AU - Chang, Wei Chao

AU - Hsu, Ming Chuan

AU - Wang, Ying Nai

AU - Cheng, Chien Chia

AU - Wei, Leizhen

AU - Nakajima, Satoshi

AU - Chang, Shih Shin

AU - Liao, Hsin Wei

AU - Chen, Chung Hsuan

AU - Lavin, Martin

AU - Ang, K. Kian

AU - Lin, Shiaw Yih

AU - Hung, Mien Chie

PY - 2015/2/5

Y1 - 2015/2/5

N2 - Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.

AB - Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.

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KW - DNA damage response

KW - EGFR

KW - tyrosine phosphorylation

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Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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