Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells
Authors: Francisca Vazquez
Tao Zou
Matthew Meyerson
Erez Y Levanon
Alexandru P Ivan
Aviad Tsherniak
Jonathan T Goldstein
Ashton C Berger
Hugh S Gannon
William C Hahn
Andrew D Cherniack
Diana Cai
Michael K Kiessling
Galen F Gao
Peter S Choi
Ilana Buchumenski
Journal: Nature Communications (2018)
Discipline: Multidisciplinary
Keywords: cancer vulnerabilities; ADAR1; interferon-stimulated genes; type I interferon signaling; protein kinase R
Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA., Department of Gastroenterology and Hepatology, University of Zurich and University Hospital Zürich, Zürich, 8091, Switzerland., Department of Medical Oncology and Hematology, University Hospital Zurich, University of Zurich, 8091, Zurich, Switzerland., The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 52900, Ramat Gan, Israel., Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA., Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. ., Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA. ., Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. ., Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Intresting paper. A small mistake, according to Fig.1C and the main text, supplementary Fig. 4a seems to be mislabeled. ![file] , 
 Sharp catch by the reader! As the reader points out, Figure 1c and Figure 1d, for example, describe these cell lines correctly as ADAR KO insensitive (NCI-H1299 and A549) and ADAR KO sensitive (HCC366, NCI-H1650, NCI-H196, NCI-H596, HCC1438, SW900, and PATU-8902), respectively. But here in Supplementary Figure 4a, we reversed the labels--calling the insensitive cell lines as  sensitive and the sensitive cell lines as  insensitive . We will contact the journal and try to get the figure corrected. ,