David Cortez
Faculty Member
Last active: 2/4/2016

Rapid activation of ATR by ionizing radiation requires ATM and Mre11.

Myers JS, Cortez D
J Biol Chem. 2006 281 (14): 9346-50

PMID: 16431910 · PMCID: PMC1821075 · DOI:10.1074/jbc.M513265200

The ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases are crucial regulatory proteins in genotoxic stress response pathways that pause the cell cycle to permit DNA repair. Here we show that Chk1 phosphorylation in response to hydroxyurea and ultraviolet radiation is ATR-dependent and ATM- and Mre11-independent. In contrast, Chk1 phosphorylation in response to ionizing radiation (IR) is dependent on ATR, ATM, and Mre11. The ATR and ATM/Mre11 pathways are generally thought to be separate with ATM activation occurring early and ATR activation occurring as a late response to double strand breaks. However, we demonstrate that ATR is activated rapidly by IR, and ATM and Mre11 enhance ATR signaling. ATR-ATR-interacting protein recruitment to double strand breaks is less efficient in the absence of ATM and Mre11. Furthermore, IR-induced replication protein A foci formation is defective in ATM- and Mre11-deficient cells. Thus, ATM and Mre11 may stimulate the ATR signaling pathway by converting DNA damage generated by IR into structures that recruit and activate ATR.

MeSH Terms (19)

Antineoplastic Agents Ataxia Telangiectasia Mutated Proteins Cell Cycle Cell Cycle Proteins Checkpoint Kinase 1 DNA-Binding Proteins DNA Damage DNA Repair Humans Hydroxyurea Kinetics MRE11 Homologue Protein Phosphorylation Protein-Serine-Threonine Kinases Protein Kinases RNA, Small Interfering Signal Transduction Transfection Tumor Suppressor Proteins

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