Tyrosine 370 Phosphorylation of Atm Positively Regulates Dna Damage Response

<p>Ataxia telangiectasia-mutated (ATM) mediates DNA damage response by controlling irradiation (IR)-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon IR stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Y370 at the site of double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, ATM Y370F mutant or pretreatment with an EGFR kinase inhibitor gefitinib blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radio-sensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response and ATM Y370 phosphorylation may serve as a biomarker for radiation and anti-EGFR combinational therapies.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Lee, Hong-Jen

Contributors dc:contributor

• Mien-Chie Hung Ph.D.
• Dihua Yu, M.D., Ph.D.
• Pierre D. McCrea, Ph.D.

• EGFR
• ATM
• DNA Damage Response
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/487

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1526