Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation.

摘要: Cells adjust to hypoxic stress within the tumor microenvironment by downregulating energy-consuming processes including translation. To delineate mechanisms of cellular adaptation hypoxia, we performed RNA-Seq normoxic and head neck cancer cells. These data revealed a significant down regulation genes known regulate RNA processing splicing. Exon-level analyses classified > 1,000 mRNAs as alternatively spliced under hypoxia uncovered unique retained intron (RI) in master regulator translation initiation, EIF2B5. Notably, this was expressed solid tumors stage-dependent manner. We investigated biological consequence RI demonstrate that its inclusion creates premature termination codon (PTC), leads 65kDa truncated protein isoform opposes full-length eIF2Be inhibit global Furthermore, expression led increased survival cells providing evidence enables adapt conditions low oxygen. Additional work uncover -cis -trans regulators EIF2B5 splicing identified several factors influence retention EIF2B5: weak potential at RI, hypoxia-induced binding factor SRSF3, total phospho-Ser2 polymerase II specifically hypoxia. Altogether, these reveal differential previously uncharacterized mode translational control are supported model which changes cotranscriptional lead selective PTC-containing