P-221 - A protective role for ATM in hemolytic conditions

Abstract

Ataxia-telangiectasia mutated (ATM) is a kinase with a central role in DNA repair, but also involved in response to other forms of stress and damage, including hypoxia and oxidative stress. Mutations in ATM trigger ataxia-telangiectasia (A-T), a pleiotropic disease typified by genomic instability, immunodeficiency, high cellular ROS, ataxia and telangiectasia. In addition, some A-T patients also display other less understood traits, including autoimmune hemolytic anemia, suggesting that ATM is important to counter the detrimental effects of hemolysis. Here we show that Atm-null mice are highly susceptible to malaria, an infection disease caused by Plasmodium spp., associated with extensive hemolysis. Similarly, these mice are also susceptible to sterile hemolysis, such as triggered by anti-mouse red blood cells serum. This supports the notion that ATM prevents damage caused by hemolysis. Whether this protective effect of ATM is related to its DNA repair function or oxidative stress is being analysed. One possibility is that ATM acts to counteract the deleterious effects of labile heme, a pathogenic byproduct of hemolysis released from oxidized extracellular hemoglobin. In conclusion, we reveal an unsuspected role for ATM in countering the pathologic effects of hemolysis.