Connecting RNA processing to metabolism, cellular homeostasis and disease

The Question

RNA processing is an umbrella-term for a large number of chemical reactions that turn precursor RNAs into mature, functional molecules. At the core of our Lab is “Non-canonical RNA splicing”, a catalytic mechanism that removes single introns and joins remaining exons, strikingly different to the mRNA-devoted spliceosome. After several years of hard work, a podium of favorite enzymes and pathways conforms the pillars of our research. Yet, with a blend of curiosity, expertise, networking and intuition, we keep digging into non-canonical RNA splicing and adventuring into new, unexpected directions.   

Having identified several players of the enzymatic machinery executing non-canonical RNA splicing, we are currently focusing on regulatory and physiological aspects of it. We discovered that the tRNA ligase complex (tRNA-LC) – a pillar of our research – is modulated by redox-mechanisms, involving metals, the antioxidant thioredoxin and the essential oxidoreductase PYROXD1, which protects the tRNA-LC against oxidation. Our current research also shows that PYROXD1 plays a critical function in iron metabolism, well beyond RNA biology. We also discovered that RNA molecules ended in 2’,3’-cyclic phosphates, substrates of the tRNA-LC, are processed by the cyclic phosphatase ANGEL2, which is itself regulated by post-translational modifications. The full interactome of the tRNA-LC and the individual roles of its subunits are also at the core of our Lab. Finally, we are making great progress in dissecting the mechanistic defects underlying Diamond Blackfan Anemia, a rare syndrome intimately linked to defects in RNA processing and iron metabolism. Please visit https://dbaexperiment.org.

Defining important as well as addressable questions is essential. We investigate, discover, communicate… and ask new questions. This is the science game that students and postdocs would enjoy when joining our group.

The Approach

Our Laboratory relies on Biochemistry and Molecular Biology to identify and characterize key players in RNA processing. We boost this “in vitro” approach with structural biology – so far through collaborations with outstanding colleagues – and the proteomics, metabolomics and next generation sequencing facilities at the Vienna BioCenter. In parallel, and when appropriate, we adventure “in vivo” to understand the role of specific RNA processing factors and ribosomal proteins in health and disease, turning into animal models – mutating or deleting involved genes – or cells from patients.