Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells.
Hugh S GannonTao ZouMichael K KiesslingGalen F GaoDiana CaiPeter S ChoiAlexandru P IvanIlana BuchumenskiAshton C BergerJonathan T GoldsteinAndrew D CherniakFrancisca VazquezAviad TsherniakErez Y LevanonWilliam C HahnMatthew L MeyersonPublished in: Nature communications (2018)
Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.
Keyphrases
- single cell
- protein kinase
- cell therapy
- genome wide
- papillary thyroid
- small molecule
- stem cells
- transcription factor
- gene expression
- cell proliferation
- poor prognosis
- machine learning
- risk assessment
- climate change
- artificial intelligence
- squamous cell
- binding protein
- rna seq
- smoking cessation
- lymph node metastasis
- human health