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NEWLY SYNTHESIZED mRNA ESCAPES TRANSLATIONAL REPRESSION DURING THE ACUTE PHASE OF THE MAMMALIAN UNFOLDED PROTEIN RESPONSE

Alzahrani, Mohammed Rubayyi
http://orcid.org/0000-0001-7291-5275
http://rave.ohiolink.edu/etdc/view?acc_num=case1670598692819292

Abstract Details

2023, Doctor of Philosophy, Case Western Reserve University, 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.
Maria Hatzoglou (Advisor)
26 p.
Molecular Biology
Poly(A) Tail Length; Translation Inhibition; mRNA Stability; ER stress; UPR; XBP1

Recommended Citations

Citations

  • Alzahrani, M. R. (2023). NEWLY SYNTHESIZED mRNA ESCAPES TRANSLATIONAL REPRESSION DURING THE ACUTE PHASE OF THE MAMMALIAN UNFOLDED PROTEIN RESPONSE [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1670598692819292

    APA Style (7th edition)

  • Alzahrani, Mohammed. NEWLY SYNTHESIZED mRNA ESCAPES TRANSLATIONAL REPRESSION DURING THE ACUTE PHASE OF THE MAMMALIAN UNFOLDED PROTEIN RESPONSE. 2023. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1670598692819292.

    MLA Style (8th edition)

  • Alzahrani, Mohammed. "NEWLY SYNTHESIZED mRNA ESCAPES TRANSLATIONAL REPRESSION DURING THE ACUTE PHASE OF THE MAMMALIAN UNFOLDED PROTEIN RESPONSE." Doctoral dissertation, Case Western Reserve University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=case1670598692819292

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.