Investigating adenosine-to-inosine modification in RNA-DNA hybrids and the innate immune response

The ability of cells to recognise pathogen-derived nucleic acids amongst self-nucleic acids, which are abundant and structurally similar, is critical for an effective innate immune system in all lifeforms. Indeed, aberrant immune activation towards self-nucleic acids can lead to deleterious autoimmunity. In vertebrates, cells chemically modify DNA and RNA nucleosides so that nucleic acid receptors can distinguish endogenous nucleic acids from those of invading pathogens. Adenosine-to-inosine (A-to-I) deamination on messenger RNA is catalysed by a family of Adenosine Deaminases Acting on RNA (ADAR). This modification acts to suppress innate immune responses to host-derived double-stranded RNAs in the cytoplasm. Recent studies have observed ADAR-catalysed A-to-I modification in RNA-DNA hybrids, which are double-stranded structures that form during transcription and DNA replication in the nucleus. However, it is unknown if A-to-I modification of hybrids occur in the cytoplasm, where these nucleic acid species can escape to and consequently induce inflammatory responses. Therefore, this project will combine molecular genetics and bioinformatic approaches to investigate A-to-I modification in cytoplasmic hybrids. Deciphering the effects of base modifications on nucleic acid recognition is fundamental to our understanding of innate immunity. This is crucial for the application of synthetic nucleic acids in genetic engineering and gene therapies.

UKRI-BBSRC Themes and Priorities
- Understanding the rules of life
- Data-driven biology
- Technology development for the biosciences