Recoding Mechanisms in Infections
Many important viruses such as Ebola, Influenza, and HIV use RNA as genetic material. These viruses have an extremely small genome size compared to the eukaryotic host genomes, and therefore employ various alternative translation strategies such as stop codon read through, leaky scanning, non-IRES initiation and ribosome frameshifting to express their genes by the host translation machinery. Interestingly, the same strategies are also used in the host’s cellular gene expression. With our research we aim to understand how translational recoding changes the rules of standard decoding, allows simultaneous encoding of multiple proteins from the same mRNA and regulates gene expression in time and space. This group is located at the Helmholtz Institute for RNA-based Infection Research (HIRI).
The central focus of my group is to identify the molecular players and mechanisms of recoding events in viral pathogens and eukaryotic host cells by using biochemical and biophysical analysis tools. Frameshifting is a translational recoding event that is used by many important pathogens (i.e. HIV, SARS –CoV and MMTV) to synthesize central genes for replication and proliferation. Frameshifts also occur in prokaryotic and eukaryotic genomes with efficiencies reaching up to 80%. In most of the cases, a fixed ratio of frameshifting is crucial for the replication and proliferation of the viruses. There is also new compelling evidence suggesting temporal regulation of frameshifting by trans-acting small RNAs and proteins. However, we still lack the detailed understanding of the roles these alternative translation events play during cellular processes and pathogenesis and how they are regulated.
Our research focuses on these unconventional translation events in RNA viruses and cellular genes to understand the mechanistic details. By characterizing the RNA interaction network of pathogens and host cells we aim to shed light on the interaction of pathogenic processes and cellular responses. Additionally, to answer the role of specific frameshifting mRNA interactions, we use a highly interdisciplinary approach that combines cutting-edge RNA analytics, such as ribosome profiling and deep sequencing, with biochemical and computational tools. Our model systems include simplified reconstituted viral and cellular components to reveal the molecular phenomena in vitro as well as whole mammalian cells to study the cellular system in vivo.
A current overview of the team and further information about the research group can be found on the HIRI page.