Volume 25, No 2, Feb 2015

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 25 Issue 2, February 2015: 225-236

ORIGINAL ARTICLES

Tyrosine 370 phosphorylation of ATM positively regulates DNA damage response

Hong-Jen Lee^1,5, Li Lan^6,7, Guang Peng⁴, Wei-Chao Chang^8,9, Ming-Chuan Hsu¹, Ying-Nai Wang^1,8, Chien-Chia Cheng¹, Leizhen Wei^6,7, Satoshi Nakajima^6,7, Shih-Shin Chang^1,5, Hsin-Wei Liao^1,5, Chung-Hsuan Chen⁹, Martin Lavin¹⁰, K Kian Ang^2,*, Shiaw-Yih Lin³ and Mien-Chie Hung^1,5,8,11

¹Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
²Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
³Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
⁴Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
⁵The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA
⁶Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA
⁷Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
⁸Graduate Institute of Cancer Biology, Center for Molecular Medicine, China Medical University, Taichung 404
⁹The Genomics Research Center, Academia Sinica, Taipei 115
¹⁰University of Queensland Centre for Clinical Research, Royal Brisbane Hospital Campus, Herston, Australia
¹¹Department of Biotechnology, Asia University, Taichung 404 Correspondence: Mien-Chie Hung,(mhung@mdanderson.org)

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.

10.1038/cr.2015.8

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