Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
Adv Sci (Weinh). 2021 Nov;8(22):e2102534. doi: 10.1002/advs.202102534. Epub 2021 Oct 18.
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.
辐射是骨髓（BM）移植和癌症治疗的重要预备程序。辐射的治疗效果和相关毒性因患者个体差异而有所不同，因此难以规定最佳的个体化照射剂量。辐射反应的分子决定因素仍不清楚。AIM2 样受体（ALR）是先天免疫的关键参与者，决定了感染、炎症性疾病、衰老和癌症的进程。本研究报道，缺乏 ALR 的小鼠对辐射诱导的 BM 损伤具有抗性。研究表明，核 ALR 是 DNA 修复的抑制剂，从而加速基因组不稳定性、微核生成和细胞死亡，并且这种新功能与其在先天免疫中的作用脱钩。从机制上讲，ALR 结合并干扰了对 DNA 修复至关重要的染色质松解。这一发现揭示了 ALR 作为针对遗传毒性组织损伤的新干预靶点，并可能作为预测放化疗结果的生物标志物。
