Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition

descriptionPublicationkeyboard_double_arrow_right Article 25 Apr 2007 Spain English Publisher:Springer Science and Business Media LLCJournal:BMC Molecular Biology, volume 8 (eissn: 1471-2199,

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Authors: Aguilar-Quesada, Rocío; Muñoz-Gámez, José Antonio; Martín-Oliva, David; Peralta, Andreína; Valenzuela, Maria Teresa; Matínez-Romero, Rubén; Quiles-Pérez, Rosa; +4 Authors

doi: 10.1186/1471-2199-8-29

pmid: 17459151

pmc: PMC1868035

handle: 10481/32744 , 10261/3414 , 10668/706

Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition

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Abstract

Abstract ATM and PARP-1 are two of the most important players in the cell's response to DNA damage. PARP-1 and ATM recognize and bound to both single and double strand DNA breaks in response to different triggers. Here we report that ATM and PARP-1 form a molecular complex in vivo in undamaged cells and this association increases after γ-irradiation. ATM is also modified by PARP-1 during DNA damage. We have also evaluated the impact of PARP-1 absence or inhibition on ATM-kinase activity and have found that while PARP-1 deficient cells display a defective ATM-kinase activity and reduced γ-H2AX foci formation in response to γ-irradiation, PARP inhibition on itself is able to activate ATM-kinase. PARP inhibition induced γ H2AX foci accumulation, in an ATM-dependent manner. Inhibition of PARP also induces DNA double strand breaks which were dependent on the presence of ATM. As consequence ATM deficient cells display an increased sensitivity to PARP inhibition. In summary our results show that while PARP-1 is needed in the response of ATM to gamma irradiation, the inhibition of PARP induces DNA double strand breaks (which are resolved in and ATM-dependent pathway) and activates ATM kinase.

Country

Spain

Related Organizations

Spanish National Research Council
Spain
University of Granada
Spain
French National Centre for Scientific Research
France
UNIVERSITE MARIE ET LOUIS PASTEUR
France
Institut des Sciences Biologiques
France

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Keywords

[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Protein Kinase, Poly (ADP-Ribose) Polymerase-1, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Poly(ADP-ribose) Polymerase Inhibitors, Protein Serine-Threonine Kinases, Antibodies, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans, Cell Line, Mice, Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line, Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines::Purine Nucleotides::Adenine Nucleotides::Adenosine Diphosphate, Parp-1, Molecular Biology, Oncogene, Serum Albumin, Mice, Knockout, Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Protein Binding, Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Tumor Suppressor Proteins, Tumor Suppressor Proteins, Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Cell Cycle Proteins, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice, Adenosine Diphosphate, DNA-Binding Proteins, Medical Subject Headings::Organisms::Eukaryota::Animals, Ataxia, Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Knockout, Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases, Poly(ADP-ribose) Polymerases, Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Glycosyltransferases::Pentosyltransferases::ADP Ribose Transferases::Poly(ADP-ribose) Polymerases, Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Damage, Research Article, DNA Damage, Protein Binding

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