Nuclear Tau, p53 and Pin1 Regulate PARN-Mediated Deadenylation and Gene Expression

Area of Science:

• Molecular Biology
• Cell Biology
• Neuroscience

Background:

• Nuclear tau's role in DNA damage response (DDR) and chromosome relaxation is not fully understood.
• Tau protein interactions with nuclear mRNA processing factors remain largely unexplored.

Purpose of the Study:

• To elucidate the mechanisms by which nuclear tau influences mRNA processing during DDR.
• To investigate the role of tau, p53, and PARN in regulating gene expression relevant to neurological disorders and cancer.

Main Methods:

• Co-immunoprecipitation assays to identify tau-interacting proteins.
• Enzyme activity assays to measure PARN deadenylase activity.
• Western blotting and RT-qPCR to analyze mRNA expression and protein phosphorylation.
• Cellular models of DNA damage response.

Main Results:

• Tau forms complexes with p53 and PARN, key factors in nuclear mRNA processing.
• Tau induces and enhances PARN activity during DDR, an effect modulated by p53 and tau phosphorylation.
• Pin1, a regulator implicated in cancer and Alzheimer's disease (AD), also influences nuclear deadenylation mediated by tau and PARN.
• Tau, Pin1, and PARN collectively target mRNAs deregulated in AD and/or cancer.

Conclusions:

• Novel nuclear functions of tau in mRNA processing and gene expression regulation are identified.
• Hyperphosphorylated tau exhibits toxic effects, potentially contributing to AD and cancer pathogenesis.
• A model is proposed where interactions between tau, p53, PARN, and Pin1 impact the transcriptome, offering insights into disease mechanisms.