Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Lee, Hong-Jen, Lan, Li, Peng, Guang, Chang, Wei-Chao, Hsu, Ming-Chuan, Wang, Ying-Nai, Cheng, Chien-Chia, Wei, Leizhen, Nakajima, Satoshi, Chang, Shih-Shin, Liao, Hsin-Wei, Chen, Chung-Hsuan, Lavin, Martin, Ang, K. Kian, Lin, Shiaw-Yih and Hung, Mien-Chie (2015) Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response. Cell Research, 25 2: 225-236. doi:10.1038/cr.2015.8


Author Lee, Hong-Jen
Lan, Li
Peng, Guang
Chang, Wei-Chao
Hsu, Ming-Chuan
Wang, Ying-Nai
Cheng, Chien-Chia
Wei, Leizhen
Nakajima, Satoshi
Chang, Shih-Shin
Liao, Hsin-Wei
Chen, Chung-Hsuan
Lavin, Martin
Ang, K. Kian
Lin, Shiaw-Yih
Hung, Mien-Chie
Title Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response
Journal name Cell Research   Check publisher's open access policy
ISSN 1001-0602
1748-7838
Publication date 2015-02-01
Year available 2015
Sub-type Article (original research)
DOI 10.1038/cr.2015.8
Open Access Status Not yet assessed
Volume 25
Issue 2
Start page 225
End page 236
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1312 Molecular Biology
1307 Cell Biology
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.
Keyword EGFR
ATM
Tyrosine phosphorylation
DNA damage response
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID AG045545-01
CA109311, CA099031, and CCSG CA1667
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2016 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 12 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 15 times in Scopus Article | Citations
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