Doctor of Philosophy, Case Western Reserve University, 2023, Biochemistry

Endoplasmic Reticulum (ER) stress, caused by the accumulation of misfolded proteins in the ER, elicits a homeostatic mechanism known as the Unfolded Protein Response (UPR). The UPR reprograms gene expression to promote adaptation to chronic ER stress. The UPR comprises an acute phase involving inhibition of bulk protein synthesis and a chronic phase of transcriptional induction coupled with the partial recovery of protein synthesis. However, the role of transcriptional regulation during the acute phase of the UPR is not well understood. In this study (Alzahrani et al., 2022), I analyzed the fate of newly synthesized mRNA encoding the protective and homeostatic transcription factor X-box binding protein 1 (XBP1) during this acute phase of UPR. Global translational repression induced during the acute UPR was documented and characterized by decreased translation and increased stability of XBP1 mRNA. My data suggest this stabilization of XBP1 mRNA is independent of new transcription. In contrast, newly synthesized XBP1 mRNA is shown to accumulate with long poly(A) tails and escapes translational repression during the acute phase of UPR. Inhibition of nascent RNA polyadenylation during the acute phase decreased cell survival with no effect in unstressed cells. During the chronic phase of the UPR, XBP1 mRNA abundance and long poly(A) tails decreased in a manner consistent with co-translational deadenylation. Finally, additional pro-survival, transcriptionally-induced genes show similar regulation, supporting the broad significance of the pre-steady state UPR in translational control during ER stress. I conclude that the biphasic regulation of poly(A) tail length during the UPR represents a previously unrecognized pro-survival mechanism of mammalian gene regulation.

Committee: Maria Hatzoglou (Advisor) Subjects: Molecular Biology