Protein - Nucleic Acids Interactions

Alekos Athanasiadis

Sequence is not fate. Proteins demonstrate an impressive ability not only to recognize and bind to particular pieces of nucleic acids code but also to alter its information content by catalysing reactions that rearrange its sequence or specifically change one nucleotide for another. Organisms have found in such mechanisms the means for creating sequence diversity as it is gloriously exemplified in the diversification of immunoglobulin genes. The recent realization that multi-cellular organisms achieve phenotypic complexity without a parallel increase in number of genes has highlighted the importance of posttranscriptional RNA modifications in creating and fine-tuning a much larger repertoire of proteins originating from a small number of genes. I am interested in the study of the molecular mechanisms involved in such diversification of RNA and DNA sequence as well as understanding the consequences of such processes for molecular evolution dynamics. In this direction I am employing the tools of computational, molecular and structural biology in the study of RNA and DNA editing. My work presently focuses on the A to I RNA editing process which alters the sequence of thousands of human pre-mRNAs (Athanasiadis et al., 2004), having this way a prominent role in regulating Innate Immune responses to dsRNA.



The A to I RNA editing process targets imperfect stem loop structures in pre-mRNAs. Such structures are ubiquitous in the transcriptome of all higher eukaryotes. We are interested in developing computational models of the enzymatic specificity for this mRNA modification and use these models to study the dynamics and evolution of novel targets of RNA editing.

The innate immunity system for vertebrates represents the front-end of their defense against invading viruses and bacteria. Its activation is based on the recognition of pathogen associated molecular patterns (PAMPs) by specialized receptors. Central in the pathogen recognition process is the detection of nucleic acids. However, how exactly foreign nucleic acids are distinguished from host DNA and RNA is poorly understood and of great importance since false recognition leads to severe auto-immune disorders. DAI is a protein which recently was identified as a receptor for dsDNA in the cytoplasm. This receptor for nucleic acids shares DNA/RNA binding domains with the interferon inducible RNA editing enzyme ADAR1. We are aiming to characterize the protein/nucleic acids interactions of this interferon response pathway by means of biochemistry and structural biology.


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