Abstract
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.
Highlights
Tau is known as a microtubule-associated protein involved in a number of neurodegenerative disorders, including Alzheimer’s disease (AD; Lee et al, 2011)
Various studies have shown that tau localizes to the nuclei of neurons (Brady et al, 1995; Greenwood and Johnson, 1995; Frost et al, 2014; Bukar Maina et al, 2016), and non-neuronal cells (Cross et al, 2000); and it can interact with different RNA-binding proteins (RBPs) participating in diverse RNA metabolic pathways (Meier et al, 2016; Vanderweyde et al, 2016; Apicco et al, 2018; Maziuk et al, 2018)
These results provide evidence that tau can associate with factors previously described to be involved in mRNA 3 processing, such as tumor suppressor p53, Pin1 and poly(A)-specific ribonuclease (PARN) deadenylase, in the nucleus, and that phosphorylation of tau at pathological sites might affect the formation of those complexes
Summary
Tau is known as a microtubule-associated protein involved in a number of neurodegenerative disorders, including Alzheimer’s disease (AD; Lee et al, 2011). In neurons of AD patients, insoluble hyperphosphorylated tau protein aggregates form intracellular lesions that accumulate into neurofibrillary tangles, known as paired helical filaments (PHFs), causing neuronal death (Lu et al, 1999; Lee et al, 2011; Beharry et al, 2014). In normal individuals, tau is a highly soluble, non-phosphorylated protein that stabilizes microtubules in the neuronal cytoplasm (Buée et al, 2000). We have shown that hyperphosphorylated tau disrupts the microtubule system and can act as a ‘‘prion-like’’ protein, inducing conformational changes in normal tau, acting as a gain of toxic function (Alonso et al, 2016). While it has been shown that hyperphosphorylated tau translocates into the nucleus (Alonso et al, 2010; Sarkar et al, 2016), only dephosphorylated tau binds to and protects neuronal DNA after oxidative and mild heat stresses, indicating that
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