Cai Xulong, Xu Qiaolan, Yin Tongjin, Li Xia, Cheng Yan, Li Xiangning, Hao Chuangli
Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China; Department of Pediatrics, Affiliated Hospital 6 of Nantong University (Yancheng Third People's Hospital), Yancheng, China.
Department of Pediatrics, Affiliated Hospital 6 of Nantong University (Yancheng Third People's Hospital), Yancheng, China.
Toxicol Lett. 2025 Jul;410:130-138. doi: 10.1016/j.toxlet.2025.06.012. Epub 2025 Jun 16.
Allergens, a common trigger of asthma, can lead to increased levels of reactive oxygen species (ROS) and subsequent DNA damage. However, the repair mechanism of DNA damage caused by oxidative stress in allergen-induced asthma is less known. We explored the mechanism by which topoisomerase 1 binding arginine/serine rich protein (TOPORS) regulates small ubiquitin-related modifier 1 (SUMO1) modification of TOP1 to repair DNA damage induced by ovalbumin (OVA). We tested the expression level of TOP1 in asthmatic and healthy children. OVA-induced mouse asthma model was used for further validation. The level of SUMO1-TOP1 in macrophages was studied by immunoprecipitation. The expression of TOP1 was increased in asthmatic children. The expression of TOP1 and γ Histone 2AX (γH2AX) were increased in the lung tissue of asthmatic mice. In OVA-induced macrophages, the levels of TOP1 and γH2AX were increased, while knockdown expression of TOP1 could reduce the level of γH2AX. The level of SUMO1-TOP1 in OVA-induced macrophages was increased. Interestingly, knockdown expression of TOPORS could reduce the levels of SUMO1-TOP1 in OVA-induced macrophages, while the levels of TOP1 and γH2AX were increased. Our results indicate that TOPORS regulates SUMO1 modification of TOP1 and plays an important role in the repair of DNA damage induced by OVA. DNA repair in asthma exacerbation could be a therapeutic target.
过敏原是哮喘的常见诱因，可导致活性氧（ROS）水平升高及随后的DNA损伤。然而，变应原诱导的哮喘中由氧化应激引起的DNA损伤修复机制尚鲜为人知。我们探究了拓扑异构酶1结合富含精氨酸/丝氨酸蛋白（TOPORS）调节TOP1的小泛素相关修饰物1（SUMO1）修饰以修复卵清蛋白（OVA）诱导的DNA损伤的机制。我们检测了哮喘患儿和健康儿童中TOP1的表达水平。使用OVA诱导的小鼠哮喘模型进行进一步验证。通过免疫沉淀研究巨噬细胞中SUMO1-TOP1的水平。哮喘患儿中TOP1的表达增加。哮喘小鼠肺组织中TOP1和γ组蛋白2AX（γH2AX）的表达增加。在OVA诱导的巨噬细胞中，TOP1和γH2AX的水平升高，而敲低TOP1的表达可降低γH2AX的水平。OVA诱导的巨噬细胞中SUMO1-TOP1的水平增加。有趣的是，敲低TOPORS的表达可降低OVA诱导的巨噬细胞中SUMO1-TOP1的水平，而TOP1和γH2AX的水平则升高。我们的结果表明，TOPORS调节TOP1的SUMO1修饰，并在OVA诱导的DNA损伤修复中起重要作用。哮喘加重期的DNA修复可能是一个治疗靶点。
