Hypoxia regulates endogenous double-stranded RNA production via reduced mitochondrial DNA transcription

Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Increasing evidence shows that hypoxia promotes local immune suppression and downregulates the expression of type I interferon (IFN) pathway which is actively involved in current anti-cancer therapies' success. It was recently described that double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activate the type I IFN pathway. The aims of this study were to determine the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer, and the mechanisms involved. A significant decrease in dsRNA production was observed in different cell lines under hypoxia in a HIF1/2a-independent manner. dsRNA from mitochondrial fraction was responsible for activation of the type I IFN and significantly decreased after hypoxia treatment. Mitochondrial encoded genes were downregulated in hypoxic samples and in dsRNA-pull-down experiments using the J2 antibody suggesting a reduction in mitochondrial transcription during hypoxia. Overall design: Sequencing of RNA extracted from MCF7 cell lines under normoxia and hypoxia conditions & those immunoprecipitated by J2 antibodies in the same cell lines in hypoxia and normoxia conditions