Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line.
Yize Henry LiShuvojit BanerjeeStephen A GoldsteinBeihua DongChristina GaughanSneha RathJesse DonovanAlexei KorennykhRobert H SilvermanSusan R WeissPublished in: eLife (2017)
ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of ADAR1 leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, Adar1 mutations are embryonic lethal but are rescued by mutation of the Mda5 or Mavs genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of ADAR1 mutation are unknown. We show that the cell-lethal phenotype of ADAR1 deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the RNASEL gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway for endogenous dsRNA that leads to cell death.
Keyphrases
- crispr cas
- cell cycle arrest
- cell death
- induced apoptosis
- endothelial cells
- genome editing
- binding protein
- single cell
- immune response
- induced pluripotent stem cells
- cell therapy
- pi k akt
- genome wide
- dendritic cells
- breast cancer cells
- poor prognosis
- oxidative stress
- endoplasmic reticulum stress
- pluripotent stem cells
- transcription factor
- gene expression
- type diabetes
- free survival
- drug induced