University of Texas Health Science Center at Houston
Tyrosine 370 Phosphorylation of Atm Positively Regulates Dna Damage Response
Abstract
dc:description.abstract<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>
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy (PhD)
- Level thesis:degree_level
- Dissertation (PhD)
- Year dc:date.available
- 2014
Author and committee
dc:creator, dc:contributor.*- 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.
Subjects
dc:subject × 4Identifiers
dc:identifier.*- Repository record dc:identifier
- https://digitalcommons.library.tmc.edu/utgsbs_dissertations/487
- OAI identifier oai:identifier
- oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1526