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Nucleic Acids Res. 2015 Mar 31;43(6):3219-36. doi: 10.1093/nar/gkv167. Epub 2015 Mar 8.

Hypoxia-induced gene expression results from selective mRNA partitioning to the endoplasmic reticulum.

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Charité - Universitätsmedizin Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, D-10117 Berlin, Germany.
University Hospital Aachen, RWTH Aachen University, Department of Intensive and Intermediate Care, Experimental Research Unit, D-52074 Aachen, Germany.
Humboldt Universität zu Berlin, Institut für Theoretische Biologie, D-10115 Berlin, Germany Charité - Universitätsmedizin Berlin, Institut für Pathologie, D-10117 Berlin, Germany.
Universitätsklinikum Jena, Klinik für Innere Medizin III, AG Experimentelle Nephrologie, D-07743 Jena, Germany.
Max Delbrück Center for Molecular Medicine, RNA Editing and Hyperexcitability Disorders Helmholtz Group, D-13125 Berlin, Germany TU Braunschweig, Zoological Institute, Division of Cell Physiology, D-38106 Braunschweig, Germany.
Hôpital Necker-Enfants Malades, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1163 and Imagine Foundation, 75015 Paris, France.
Charité - Universitätsmedizin Berlin, Institut für Vegetative Physiologie, Charitéplatz 1, D-10117 Berlin, Germany


Protein synthesis is a primary energy-consuming process in the cell. Therefore, under hypoxic conditions, rapid inhibition of global mRNA translation represents a major protective strategy to maintain energy metabolism. How some mRNAs, especially those that encode crucial survival factors, continue to be efficiently translated in hypoxia is not completely understood. By comparing specific transcript levels in ribonucleoprotein complexes, cytoplasmic polysomes and endoplasmic reticulum (ER)-bound ribosomes, we show that the synthesis of proteins encoded by hypoxia marker genes is favoured at the ER in hypoxia. Gene expression profiling revealed that transcripts particularly increased by the HIF-1 transcription factor network show hypoxia-induced enrichment at the ER. We found that mRNAs favourably translated at the ER have higher conservation scores for both the 5'- and 3'-untranslated regions (UTRs) and contain less upstream initiation codons (uAUGs), indicating the significance of these sequence elements for sustained mRNA translation under hypoxic conditions. Furthermore, we found enrichment of specific cis-elements in mRNA 5'- as well as 3'-UTRs that mediate transcript localization to the ER in hypoxia. We conclude that transcriptome partitioning between the cytoplasm and the ER permits selective mRNA translation under conditions of energy shortage.

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