Defining the functions of A-to-I RNA editing by ADAR proteins

Our work is focused on understanding the roles and functions of A-to-I RNA editing by the ADAR family of proteins. ADAR proteins can bind to RNA and change adenosine bases to inosine – essentially changing the sequence of the RNA from that encoded in the DNA. There is a rapidly expanding understanding of the roles of ADARs, particularly ADAR1. Our work has made key biological findings that are impacting the understanding of ADAR1’s functions in diverse settings, including cancer, immunotherapy, behaviour and immunology. 

 A key function of ADAR1 is to prevent the cell’s own RNA being immunogenic (essentially, the cell’s own RNA being perceived as a virus). Editing by ADAR1 is essential, so that cells can tell the difference between RNAs that are made by the cell (and not a threat), and nucleic acids derived from pathogens such as viruses that invade the cell. We know that when this process goes wrong it can have deadly consequences in humans, exemplified by Aicardi-Goutieres Syndrome (AGS) and autoimmunity.  

 We have determined that a specific RNA modification termed Adenosine-to-Inosine (A-to-I) editing is a key regulator of the cell’s ability to discriminate “self” from “non-self” RNA. A-to-I editing is mediated by ADAR enzymes, with ADAR1 activity critical for this immune sensing pathway. We will use genome-wide screens and functional genomics to define the depth and breadth of the cellular network that can regulate the immunogenicity of the cell’s own RNA. We will use genetics, transcriptomics and saturation mutagenesis to understand how these proteins interact and modulate immunogenicity of self RNA. This will be key to understanding how the innate immune system detects RNA and how we can promote or suppress this response. 

 We use mouse models, cell culture, molecular and biochemical techniques to understand how ADAR1 – its editing activity or its specific isoforms – contribute to how cells deal with their own dsRNA.  

Projects include: 

• Characterise new functions of ADAR1 in vivo 
• Comparing the effects and roles of the two isoforms of ADAR1, p110 and p150, using genetic models and RNA-sequencing 
• Understanding how A-to-I RNA editing affects complex behaviours 

 Techniques – RNA biology, genetics, cell culture, molecular biology, biochemistry, CRISPR/Cas9, genome-wide screening, bioinformatics.