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 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

ATM form a complex with PARP-1 in DNA that is much more evident after treatment with DNA damaging agents

<p><b>Copyright information:</b></p><p>Taken from "Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition"</p><p>http://www.biomedcentral.com/1471-2199/8/29</p><p>BMC Molecular Biology 2007;8():29-29.</p><p>Published online 25 Apr 2007</p><p>PMCID:PMC1868035.</p><p></p> A: ATM was immunoprecipitated in human melanoma cell lines G361 and HT144 (ATM deficient) as explained under methods and the presence of PARP-1 was tested by immunoblot analysis. Cells were treated with 10 Gy IR or 2 mM MNU for 30 min. In the left panel, PARP-1 was immunoprecipitated from G361 cells treated or not with 2 mM MNU and western blot was performed to reveal ATM. B: Double indirect immunofluorescence in 3T3 fibroblasts (+/+)of PARP-1 (red signal) and ATM (green). Yellow signal correspond with co-localization of both proteins