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.
","abstract_html":"<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>","abstract_has_math":false,"creators":["Lee, Hong-Jen"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Mien-Chie Hung Ph.D.","Dihua Yu, M.D., Ph.D.","Pierre D. McCrea, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-08-01T07:00:00Z","date_published":"2014-08-01T07:00:00Z","updated_at":"2026-07-24T05:50:31Z","subjects":["EGFR","ATM","DNA Damage Response","Cancer Biology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/487","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Mien-Chie Hung Ph.D.","Dihua Yu, M.D., Ph.D.","Pierre D. McCrea, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Lee, Hong-Jen"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2015-08-05T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["EGFR","ATM","DNA Damage Response","Cancer Biology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/487"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Tyrosine 370 Phosphorylation of Atm Positively Regulates Dna Damage Response"]}]}],"canonical_facts":{"dc:contributor":["Mien-Chie Hung Ph.D.","Dihua Yu, M.D., Ph.D.","Pierre D. McCrea, Ph.D."],"dc:creator":["Lee, Hong-Jen"],"dc:date.available":["2015-08-05T07:00:00Z"],"dc:description.abstract":["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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/487"],"dc:subject":["EGFR","ATM","DNA Damage Response","Cancer Biology"],"dc:title":["Tyrosine 370 Phosphorylation of Atm Positively Regulates Dna Damage Response"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:31Z"}