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Radiation is an essential preparative procedure for bone marrow (BM) transplantation and cancer treatment. The therapeutic efficacy of radiation and associated toxicity varies from patient to patient, making it difficult to prescribe an optimal patient-specific irradiation dose. The molecular determinants of radiation response remain unclear. AIM2-like receptors (ALRs) are key players in innate immunity and determine the course of infections, inflammatory diseases, senescence, and cancer. Here it is reported that mice lacking ALRs are resistant to irradiation-induced BM injury. It is shown that nuclear ALRs are inhibitors of DNA repair, thereby accelerate genome destabilization, micronuclei generation, and cell death, and that this novel function is uncoupled from their role in innate immunity. Mechanistically, ALRs bind to and interfere with chromatin decompaction vital for DNA repair. The finding uncovers ALRs as targets for new interventions against genotoxic tissue injury and as possible biomarkers for predicting the outcome of radio/chemotherapy.

Dear Editor,Radiation sickness is a major health concern. 1 The quest for radiation countermeasures started in the wake of the devastation witnessed following the nuclear detonations during the Second World War and has continued through the subsequent radiological accidents around the world. A radioprotector is also required for prophylactic use by staff working at radiation sources, pilots, and astronauts at high risk of space radiation, or patients undertaking lengthy radiological procedures. Despite decades of research, a safe, efficient, and cost-effective radioprotector is yet to be unveiled.Acetylsalicylic acid (aspirin) is the oldest drug in the history of medicine. It has been used for over 4000 years for the treatment of pain, inflammation, fever, and more recently for cardiovascular prophylaxis 2 and cancer prevention. 3 Bone marrow failure is the primary cause of mortality following irradiation. Hence, protecting the bone marrow is a primary goal in the development of radiation countermeasures. Inflammation is a key outcome and driver of irradiation-induced tissue injury. 4 Given its anti-inflammatory effects, we inquired whether aspirin could protect against radiation. When inoculated into mice, aspirin protected against irradiation-induced bone marrow ablation (Fig. 1a; Supplementary information, Fig. S1a-d) and suppressed the induction of inflammatory genes including Ifnb1, Mx1 and Tnfa in vivo and in bone marrow-derived monocytes (BMDMos) (Supplementary information, Figs. S1e-g and S2a-c).

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