Date of Degree

2-2018

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Frida E. Kleiman

Committee Members

Alejandra Alonso

Maria Figueiredo-Pereira

David Jeruzalmi

Hualin Zhong

Subject Categories

Biochemistry

Keywords

Gene expression control, DNA damage response, mRNA 3' end processing, Post-transcription, deadenylation, mRNA 3' cleavage, tau, PARN deadenylase, p53, Pin1, RNAPII

Abstract

ABSTRACT

mRNA 3’ end processing, an essential step in eukaryotic RNA metabolism, regulates the steady-state levels of different mRNAs and contributes to the cells rapid response to stress. Studies have described potential contributions of mRNA 3’ end processing to numerous human diseases, including cancer and Alzheimer’s disease (AD). Therefore, the main purpose of this dissertation is to further elucidate some of the roles of disease-related factors Pin1, p53 and tau in the regulation mRNA 3’ end processing in non-neuronal cells under different cellular conditions, including during the DNA damage response (DDR).

The results from Chapter II show that the prolyl isomerase Pin1, a mitotic regulator overexpressed in most human cancers and depleted in the brains of AD patients, enhances nuclear deadenylase activity during DDR. Interestingly, p53 expression, a Pin1 substrate, is necessary to detect this Pin1-mediated activation in non-neuronal cells. Chapter III confirms that tau, a microtubule-associated protein involved in a number of neurodegenerative disorders including AD and a Pin1 substrate, is present in the nucleus of non-neuronal cells where it associates with Pin1, p53 and PARN to regulate mRNA 3’ end processing under non-stress and DDR conditions. More specifically, I demonstrate that tau expression induces PARN deadenylase activity, and that this p53-dependent increase is lost with phosphorylation at certain tau residues implicated in neurological diseases. Additionally, Chapter IV shows evidence that Pin1 and tau also inhibit the mRNA 3’ cleavage step of the polyadenylation reaction during DDR. Extending from results collected in previous microarray analysis, I show in Chapter V that the expression of a group of mRNAs deregulated in AD and/or cancer are targeted by Pin1, tau and PARN, supporting overlapping functions for these factors in the nucleus of non-neuronal cells. Finally, Chapter VI confirms potential roles of tau and p53 in the regulation of the protein and mRNA expression levels of each other, and extends the functional connections between these two disease-related factors in non-neuronal cells.

These findings identify novel biological roles of Pin1 and tau and highlight other possible toxicity effects of hyperphosphorylated-tau forms in the nucleus of non-neuronal cells. They also suggest that factors involved in cancer and AD might play a role in regulating gene expression by a functional interaction with the mRNA 3’ processing machinery in different conditions, resulting in specific gene expression patterns. In that scenario it is possible that tau phosphorylation and localization in neurons might play a key role in controlling gene expression, affecting the cellular transcriptome before the appearance of traditional markers of disease.

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