论文标题
TAU在DNA损伤响应期间影响p53功能和细胞命运
Tau affects P53 function and cell fate during the DNA damage response
论文作者
论文摘要
细胞不断暴露于DNA破坏损伤。为了保护生物体，细胞形成了由DNA修复，细胞分裂和细胞命运的主要调节剂p53协调的复杂分子反应。 DNA损伤积累和异常细胞命运决定可能代表了与衰老相关的疾病（如癌症和神经退行性疾病）共享的病理机制。在这里，我们在Tauopathies的背景下检查了这一假设，这是一种以Tau蛋白沉积为特征的神经退行性疾病组。为此，在神经母细胞瘤细胞中研究了对急性DNA损伤的反应，作为功能丧失的模型。在这些条件下，p53稳定性和活性改变导致细胞死亡减少和细胞衰老增加。 TAU的新发现功能涉及p53及其E3泛素连接酶MDM2的异常修饰。考虑到由神经变性和癌症引起的巨大社会影响的医疗需求，我们的研究可能会改革我们改善疾病疗法的方法。
Cells are constantly exposed to DNA damaging insults. To protect the organism, cells developed a complex molecular response coordinated by P53, the master regulator of DNA repair, cell division and cell fate. DNA damage accumulation and abnormal cell fate decision may represent a pathomechanism shared by aging-associated disorders such as cancer and neurodegeneration. Here, we examined this hypothesis in the context of tauopathies, a neurodegenerative disorder group characterized by Tau protein deposition. For this, the response to an acute DNA damage was studied in neuroblastoma cells with depleted Tau, as a model of loss-of-function. Under these conditions, altered P53 stability and activity result in reduced cell death and increased cell senescence. This newly discovered function of Tau involves abnormal modification of P53 and its E3 ubiquitin ligase MDM2. Considering the medical need with vast social implications caused by neurodegeneration and cancer, our study may reform our approach to disease-modifying therapies.
