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The eukaryotic ribosome is a complex molecular machine responsible for the translation of mRNA to protein. Over the years we have gained detailed knowledge of ribosome structure, function, and biogenesis; however, a major unanswered question in the translation field is how cells monitor the integrity of the ribosome itself. Alterations in ribosome structure and function have been associated with diseases such as neurodegeneration, cancer and ribosomopathies. Indeed, mutations, environmental stress, or mistakes during assembly can lead to malfunctioning ribosomes that need to be detected and marked for degradation to maintain translation fidelity. My group capitalizes on the recent advances in quantitative mass spectrometry, functional genomics methods, and CRISPR-mediated genome editing to study the molecular mechanisms of ribosome surveillance.
- Ribosome surveillance during biogenesis - the assembly of the eukaryotic ribosome requires more than 200 accessory factors and numerous error-prone steps. Faulty intermediates resulting from mistakes during biogenesis are rapidly degraded, affirming the existence of a quality control pathway(s) monitoring ribosome assembly. In order to identify factors that differentiate between accurate and dead-end intermediates, we are developing novel systems to model ribosome biogenesis failure.
- Ribosome damage – the ribosome is one of the most complex and long-lived machines in the cell and its many components are subject to both mechanical and chemical assaults. Accumulated damage can render the ribosome elongation incompetent, causing it to stall on messages. We are interested in identifying the molecular pathways that cope with such damaged ribosomes.
- Ribosome regulation on the organismal level – we want to build on our studies of ribosome surveillance and understand how the pathways identified in cultured cell lines contribute to the development of an intact organism. We use zebrafish as a model system to study how the integrity of the translation apparatus is monitored during development, and how dysregulation of the ribosome surveillance pathways leads to complex disease.