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

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.

Radiation-induced mitotic catastrophe in PARG-deficient cells

“…ATM activation has been proposed to result from changes in chromatin structure, independently of DNA damage (Bakkenist and Kastan, 2003;Soutoglou and Misteli, 2008), a phenomenon that probably occurs in PARG KD cells, supported by the established role of PAR in the modulation of chromatin superstructure. In addition, a functional interplay between PARP1 activity and ATM activity has been reported (Aguilar-Quesada et al, 2007;Haince et al, 2007), supporting the correlation between PAR accumulation and ATM activation observed in PARG-depleted cells.…”

A Wheat SIMILAR TO RCD-ONE Gene Enhances Seedling Growth and Abiotic Stress Resistance by Modulating Redox Homeostasis and Maintaining Genomic Integrity

“…Here, SCGE analysis suggested that the higher PARP activity ( Figure 7A) in Ta-sro1 OE transgenic plants helped maintain DNA integrity by enhancing the activity of the DNA repair machinery (Figure 10). In mammalian cells, PARP-1 could interact directly with ATM (for Ataxia-Telangiectasia mutated), an important sensor of ROS (Guo et al, 2010), and form a large protein complex to function in DNA repair and maintenance of genomic integrity through its PARP activity (Aguilar-Quesada et al, 2007;Gagné et al, 2008). In our study, At-ATM had a higher expression level in Arabidopsis Ta-sro1 OE lines than in the VC line under both NaCl and H 2 O 2 treatments (Supplemental Figure 10).…”

ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy

“…One speculative possibility is that ROS-induced DNA damage and PARP-1 overactivation caused mitochondrial dysfunction and Ca 2+ release, thereby activating AMPK [14]. Other possibility that may explain how PARP-1 connects with the AMPK/mTOR signaling (besides the maintenance of the energy status) is that PARP inactivation leads to unefficient ATM response that has been reported to be involved in the activation of AMPK [26,27].…”