TI - Discussion . AB - Cells have evolved various sophisticated pathways to sense and overcome DNA damage as a mechanism to preserve the integrity of the genome . Environmental attacks like radiations or toxins , or spontaneous DNA lesions , trigger checkpoint activation and consequent cell cycle arrest leading to DNA repair or apoptosis . Two key proteins that coordinate recognition of DNA damage and signal transduction to p53 are ATM and PARP-1 . ATM and PARP-1 participate in distinct forms of DNA repair that partially compensate for each other . PARP-1 and ATM participate in base excision repair ( BER ) and homologous recombination ( HR ) , respectively . It is normally assumed that ATM signals for double strand breaks while PARP-1 participates in signalling from single DNA strand lesions . Here we report that these two proteins form a molecular complex that co-localizes in DNA damage foci . Considerable evidence from in vitro , cell culture and ex vivo studies shows that poly ( ADP-ribosyl ) ation plays a critical role in the survival and maintenance of genomic stability of proliferating cells exposed to low or moderate levels of DNA-damaging agents [18] . The data presented in this study strongly support a role for PARP-1 and poly ( ADP-ribose ) in ATM activation : in the absence of PARP-1 there is a deficient ATM-kinase activation in response to ionizing radiation as measured by intrinsic kinase activity and H2AX PHOSphorylation . These results are in agreement with previous data showing that PARP-1 deficient mice are extremely sensitive to low doses of gamma-radiation ( as is the case for ATM-null mice ) , and this phenotype could be adscribed to a deficient ATM-kinase activation in tissues such as the intestine epithelium [9] . Also , results from our group have shown that p53 accumulation and p53 -dependent gene activation are compromised in parp-1 knockout cells after gamma-irradiation [15] . The insight of the consequences of the poly ( ADP-ribosyl ) ation of ATM are not clear yet since the inhibition of PARP induced indirectly DNA DSB , initiating new responses to DNA damage that interfere with elucidation of the activation of ATM . PARP inhibitors have been used as radio and chemo-sensitizers in a number of experimental settings and a mechanism for DSB induction through the collision of unrepaired single DNA strand lesions with replication forks has been suggested [19,20] . Early reports claimed that the PARP inhibitor 3-aminobenzamide was a radio-sensitizer only in rodent cells [21] however more recently ANI ( 1000-fold more potent at inhibiting PARP activity compared with 3-aminobenzamide ( 3-ABA ) ) has been found to be radiation sensitizer to both rodent and human tumor cells [9,15,22] . The novel PARP inhibitor AG14361 has shown to increase the specificity and in vivo activity to enhance radiation therapy of human cancer through vasoactive effects and not directly in the cells in culture [23] . Therefore the question still remains open as to how human tumors could benefit from PARP inhibition during radiotherapy . The second main conclusion in this study is that inhibition of PARP-1 activity leads to DSBs induction and activation of ATM and , at the same time , prevents IR -induced ATM-kinase activity . From the results presented here , there is a clear duality in the effect of PARP inhibition on ATM : while the lack of response to IR in ANI treated cells indicates that poly ( ADP-rybosylation ) of ATM is probably needed for optimal ATM activation , long term exposure to PARP inhibitor results in the generation of DSBs and secondarily in the activation of ATM kinase . DSBs generated in this way are due to stalled replication fork [24] and they are resolved by homologous recombination ( HR ) , providing a therapeutic opportunity to specifically kill HR deficient tumor cells , as has been previously shown by different laboratories [25,26] . In summary , our study demonstrates a strong association between ATM and PARP-1 during the response to ionizing radiation , being PARP-1 and its activity needed for optimal activation of ATM kinase . On the other hand , inhibition of PARP leads to the activation of ATM kinase as result of the generation of DSBs , making ATM deficient cells particularly sensitive to PARP inhibitors .