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Frida E. Kleiman

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Control of gene expression by regulating mRNA stability after DNA damage has the potential to contribute to the cells rapid response to stress. The main focus of this dissertation is to elucidate the role(s) of nuclear PARN deadenylase in controlling mRNA stability, hence gene expression, of factors in the p53 signaling pathway during the DNA damage response (DDR). Understanding the mechanisms of these regulatory pathways will provide new insights on how the control of gene expression upon DNA damage decides cellular fate, offering new opportunities for therapeutics. In Chapter II, I presented evidence that PARN along with the cleavage factor CstF-associated tumor suppressor BARD1 participates in the regulation of endogenous transcripts in different cellular conditions. In Chapter III, I identified the mRNA targets of PARN in non-stress conditions, and contributed to describing a feedback loop between p53 and PARN, in which PARN deadenylase keeps p53 levels low by destabilizing p53 mRNA through its 3Oe untranslated region (3fUTR) in non-stress conditions, and the UV-induced increase in p53 activates PARN, regulating gene expression during DDR in a transactivation-independent manner. In Chapter IV, I presented evidence that PARN deadenylase has a specific effect on the steady-state levels of not only AU-rich element-containing but also microRNA (miRNA)-regulated nuclear mRNAs. I showed that the functional interaction of PARN with miRNA-induced silencing complex contributes to p53 mRNA stability regulation. These studies provide the first description of PARN deadenylase function in miRNA-dependent control of mRNA decay and of miRNA-function in the nucleus. Finally, in Chapter V, I determine that nucleolin is one of the RNA binding proteins that recruits PARN to the p53 mRNA and this can be regulated by phosphorylation, representing a novel regulatory mechanism for p53 gene expression. The data presented in this dissertation has contributed to describe and comprehend some novel mechanisms behind the regulation of gene expression during DDR.

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Biochemistry Commons