Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells

Hugh S. Gannon, Tao Zou, Michael K. Kiessling, Galen F. Gao, Diana Cai, Peter S. Choi, Alexandru P. Ivan, Ilana Buchumenski, Ashton C. Berger, Jonathan T. Goldstein, Andrew D. Cherniack, Francisca Vazquez, Aviad Tsherniak, Erez Y. Levanon, William C. Hahn, Matthew Meyerson

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

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.

Original languageEnglish
Article number5450
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).

Fingerprint

Dive into the research topics of 'Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells'. Together they form a unique fingerprint.

Cite this