Abstract
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.
Highlights
Cells are constantly exposed to DNA damaging insults
Together with chromosomal abnormalities found in Alzheimer’s disease (AD)-derived fibroblasts[14] and increased DNA damage in AD brains[15,16], the emerging function of Tau in DNA stability offers an alternative role of Tau in neurodegeneration and, importantly and insufficiently investigated, in the DNA damage response (DDR)
We demonstrate that Tau deficiency renders cells less sensitive to DNA damage-induced apoptosis, which is counterbalanced by increased senescence
Summary
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. We examined this hypothesis in the context of tauopathies, a neurodegenerative disorder group characterized by Tau protein deposition. 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. We demonstrate that Tau deficiency renders cells less sensitive to DNA damage-induced apoptosis, which is counterbalanced by increased senescence We show that this activity of Tau is mediated through a P53 modulation. Our findings propose a role of P53 in tauopathies and a role of Tau in P53 dysregulation, a key event in oncogenesis
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