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

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...

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Bibliographic Details
Published in:BMC molecular biology 2007-04, Vol.8 (1), p.29-29, Article 29
Main Authors: Aguilar-Quesada, Rocío, Muñoz-Gámez, José Antonio, Martín-Oliva, David, Peralta, Andreína, Valenzuela, Maria Teresa, Matínez-Romero, Rubén, Quiles-Pérez, Rosa, Menissier-de Murcia, Josiane, de Murcia, Gilbert, Ruiz de Almodóvar, Mariano, Oliver, F Javier
Format: Article
Language:English
Subjects:
Adenosine Diphosphate
Adenosine Diphosphate - metabolism
Animals
Ataxia telangiectasia
Ataxia Telangiectasia Mutated Proteins
Biochemistry, Molecular Biology
Cell Cycle Proteins
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line
DNA Damage
DNA-Binding Proteins
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Humans
Life Sciences
Mice
Mice, Knockout
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
Poly(ADP-ribose) Polymerases - deficiency
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Protein Binding
Protein kinases
Protein-Serine-Threonine Kinases
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Ribose
Structural Biology
Tumor Suppressor Proteins
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary: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 gamma-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 gamma-H2AX foci formation in response to gamma-irradiation, PARP inhibition on itself is able to activate ATM-kinase. PARP inhibition induced gamma 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.
ISSN:1471-2199
1471-2199
DOI:10.1186/1471-2199-8-29