Mitochondrial Double-Stranded RNA Induces APOBEC3A Expression
The single-stranded DNA deaminase APOBEC3A (A3A) is a source of mutation in cancer. As an antiviral enzyme, A3A is also upregulated in response to viral infections. However, A3A upregulation is frequently observed in cancers without any obvious source of viral infection. Cellular responses to viral infections are often triggered by the sensing of nucleic acids. While these nucleic acids are usually of viral origin, endogenous nucleic acids may be mistaken as foreign and trigger these same responses, potentially leading to aberrant A3A expression. Mitochondria are one source of potentially immunogenic endogenous nucleic acids. Due to the circular nature of mitochondrial DNA, mitochondrial (mt)dsRNA is often produced during transcription. Knockdown of the enzymes (PNPase and SUV3) responsible for degrading this dsRNA results in large amounts of mtdsRNA which has the potential to activate nucleic acid sensors when leaked into the cytosol. Knockdown of PNPase triggers increases in A3A and A3B expression. Furthermore, cytoplasmic mtdsRNA potentiates a type I interferon response through the RIG-I/MAVS-axis in a STAT2 dependent manner. Although A3A appears primarily cytoplasmic under these conditions, genomic DNA damage occurs following pathway activation. Thus, mtdsRNA dysregulation could contribute to the overall mutational landscape of cancer.