Tau affects P53 function and cell fate during the DNA damage response

Neurodegeneration and cancer may share a common pathomechanism of defective cell-cycle control as a consequence of age-dependent accumulation of DNA damage. The response to DNA damage is controlled by the tumor suppressor P53 that coordinates a complex network of cellular pathways. We investigated whether the protein Tau changes the response of cells exposed to acute DNA damage. We report that Tau depletion in neuroblastoma cells severely dysregulate P53 activity and leads to reduced cell death counterbalanced by increased cell senescence. A transcriptome analysis confirms that Tau is a modifier of P53 activity regulating pro-inflammatory and cellular senescence pathways. Tau expression inversely associated to senescence in cancer, implying a relevance of our findings in the clinical population. Considering the medical need with vast social implications caused by neurodegenerative tauopathies and cancer, our study may lead to innovative approaches for disease-modifying therapies. Tau-KO clonal lines were generated using the CRISPR/Cas9 DNA-editing technology: The two gRNAs 231 and 232 targeted exon 2 containing the initiating ATG (ENST00000344290.9). Cells in 6-well plates were transfected with the plasmid kindly provided by Dr. Zhang (52961, Addgene) driving expression of one of the two gRNA, Cas9 nuclease and puromycin resistance. One day post-transfection, cells were transferred to 10 cm plates and incubated for two days with 20 ug/mL puromycin (P8833, Sigma-Aldrich). Single colonies were isolated, amplified, and stored in liquid nitrogen. Tau-KO cells 231K and 231P cells were obtained from gRNA 231 while Tau-KO cells 232P were obtained from gRNA 232. The 231A cell line underwent an unsuccessful CRISPR-Cas9 procedure (gRNA 231) and had normal Tau expression