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

While nuclear tau plays a role in DNA damage response (DDR) and chromosome relaxation, the mechanisms behind these functions are not fully understood. Here, we show that tau forms complex(es) with factors involved in nuclear mRNA processing such as tumor suppressor p53 and poly(A)-specific ribonucle...

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Bibliographic Details
Published in:Frontiers in molecular neuroscience 2019-10, Vol.12, p.242
Main Authors: Baquero, Jorge, Varriano, Sophia, Ordonez, Martha, Kuczaj, Pawel, Murphy, Michael R, Aruggoda, Gamage, Lundine, Devon, Morozova, Viktoriya, Makki, Ali Elhadi, Alonso, Alejandra Del C, Kleiman, Frida E
Format: Article
Language:English
Subjects:
Alzheimer's disease
Breast cancer
Cancer
Cell cycle
cellular DNA damage
Deoxyribonucleic acid
DNA
DNA damage
Gene expression
Kinases
Metabolism
mRNA processing
Neurodegeneration
Neurological diseases
Neuroscience
nuclear tau
p53
p53 Protein
Phosphorylation
Pin1
Pin1 protein
Proteins
Tau protein
Tumor suppressor genes
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Summary:While nuclear tau plays a role in DNA damage response (DDR) and chromosome relaxation, the mechanisms behind these functions are not fully understood. Here, we show that tau forms complex(es) with factors involved in nuclear mRNA processing such as tumor suppressor p53 and poly(A)-specific ribonuclease (PARN) deadenylase. Tau induces PARN activity in different cellular models during DDR, and this activation is further increased by p53 and inhibited by tau phosphorylation at residues implicated in neurological disorders. Tau's binding factor Pin1, a mitotic regulator overexpressed in cancer and depleted in Alzheimer's disease (AD), also plays a role in the activation of nuclear deadenylation. Tau, Pin1 and PARN target the expression of mRNAs deregulated in AD and/or cancer. Our findings identify novel biological roles of tau and toxic effects of hyperphosphorylated-tau. We propose a model in which factors involved in cancer and AD regulate gene expression by interactions with the mRNA processing machinery, affecting the transcriptome and suggesting insights into alternative mechanisms for the initiation and/or developments of these diseases.
ISSN:1662-5099
1662-5099
DOI:10.3389/fnmol.2019.00242