The Overall Objective of the proposed investigation is to elucidate the role of the interferon-inducible RNA-specific adenosine deaminase (ADAR1) in the actions that interferons (IFN) mediate on viral and host functions.
The Specific Aims of our proposed continuation study of ADAR1 and double-stranded RNA editing in IFN action are as follows: (1) To further characterize the biochemical and biophysical properties of the IFN-inducible p150 ADAR1. To determine the mechanisms by which poxvirus E3L protein and adenovirus VA1 RNA antagonize ADAR1 enzymatic activity; to characterize the functional selectivity of dsRNA binding domains of ADAR1; and to determine the structural basis and functional significance of ADAR1 protein interactions and subcellular localizations in uninfected and virus-infected cells. (2) To further delineate the structure of the 5'-flanking regions of the ADAR1 gene required for IFN-inducible and basal transcriptional activity, including the Pi promoter responsible for inducible expression of transcripts encoding the p150 ADAR1 protein isoform and the Pb and Pc promoters responsible for constitutive expression of nuclear p110 ADAR1. To define the pathways leading to inducible transcriptional activation of ADAR1 expression in IFN-treated cells and in infected mice. (3) To further characterize the effect of singular stable expression of wild type and mutant forms of ADAR1 deaminase in cultured cells on virus multiplication including VA1 mutant adenovirus, E3L mutant vaccinia virus and recombinant measles virus, to generate a targeted deletion of the mouse ADAR1 inducible genomic locus, and to determine the effect of the ADAR1 p150 disruption on mouse phenotype and viral pathogenesis. The health relatedness of the proposed research stems from the likelihood that the work may contribute to a better understanding of regulatory mechanisms operative in normal cells as well as virus-infected cells. Furthermore, elucidation of the actions of IFN at the molecular level is of importance in view of potential applications of interferon in the clinic.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Virology - B Study Section (VIRB)
Program Officer
Cassetti, Cristina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
Zip Code
Tan, Meng How; Li, Qin; Shanmugam, Raghuvaran et al. (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254
George, Cyril X; Ramaswami, Gokul; Li, Jin Billy et al. (2016) Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses. J Biol Chem 291:6158-68
George, Cyril X; Samuel, Charles E (2015) STAT2-dependent induction of RNA adenosine deaminase ADAR1 by type I interferon differs between mouse and human cells in the requirement for STAT1. Virology 485:363-70
Pfaller, Christian K; Mastorakos, George M; Matchett, William E et al. (2015) Measles Virus Defective Interfering RNAs Are Generated Frequently and Early in the Absence of C Protein and Can Be Destabilized by Adenosine Deaminase Acting on RNA-1-Like Hypermutations. J Virol 89:7735-47
Pfaller, Christian K; Radeke, Monte J; Cattaneo, Roberto et al. (2014) Measles virus C protein impairs production of defective copyback double-stranded viral RNA and activation of protein kinase R. J Virol 88:456-68
John, Lijo; Samuel, Charles E (2014) Induction of stress granules by interferon and down-regulation by the cellular RNA adenosine deaminase ADAR1. Virology 454-455:299-310
Okonski, Kristina M; Samuel, Charles E (2013) Stress granule formation induced by measles virus is protein kinase PKR dependent and impaired by RNA adenosine deaminase ADAR1. J Virol 87:756-66
Taghavi, Nora; Samuel, Charles E (2013) RNA-dependent protein kinase PKR and the Z-DNA binding orthologue PKZ differ in their capacity to mediate initiation factor eIF2?-dependent inhibition of protein synthesis and virus-induced stress granule formation. Virology 443:48-58
Ruggieri, Alessia; Dazert, Eva; Metz, Philippe et al. (2012) Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection. Cell Host Microbe 12:71-85
Taghavi, Nora; Samuel, Charles E (2012) Protein kinase PKR catalytic activity is required for the PKR-dependent activation of mitogen-activated protein kinases and amplification of interferon beta induction following virus infection. Virology 427:208-16

Showing the most recent 10 out of 102 publications