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Hypoxia Influences Polysome Distribution of Human Ribosomal Protein S12 and Alternative Splicing of Ribosomal Protein mRNAs

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Title: Hypoxia Influences Polysome Distribution of Human Ribosomal Protein S12 and Alternative Splicing of Ribosomal Protein mRNAs
Author: Brumwell, Andrea
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Uniacke, James
Abstract: Ribosomes were once considered static in composition because of their essential role in protein synthesis and kingdom-wide conservation. This view is changing however, as mutations in certain ribosomal proteins are tolerated by cells, albeit with disease phenotypes known as “ribosomopathies”. Heterogeneity in the protein composition of eukaryotic ribosomes is an emerging concept with evidence that different pools of ribosomes exist with transcript-specificity, although evidence in human cells is severely lacking. Furthermore, the influence of a physiological stressor on human ribosomal proteins has yet to be studied. We show that the polysome association of human RPS12 (eS12) is altered by low oxygen (hypoxia), a feature of the tumor microenvironment. Our data suggest that RPS12 (eS12) is enriched in hypoxic monosomes, which increases the heavy polysome association of structured transcripts APAF-1 and XIAP. We also show that alternative splicing of RPS24 (eS24) is substantially altered in cell culture models of tumor hypoxia (spheroids), which may be partly influenced by hypoxia and acidosis. Since APAF-1 and XIAP play opposing roles in apoptosis, these data may help to further understand cell death under stress. Additionally, alternative splicing of RPS24 changes the coding sequence, thus could provide heterogeneity to ribosomes as an adaptation to the spheroid/tumor microenvironment. Our data suggest that features of the tumor microenvironment, including hypoxia, may influence regulation of the human ribosome through changes in RP incorporation and the production of stress-specific RP isoforms.
URI: http://hdl.handle.net/10214/18055
Date: 2020-06
Rights: Attribution 4.0 International
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