description
- Plants underpin many of the proposed climate change mitigation strategies and are crucial for improving food, energy and water security. Despite this, basic research in plants is hampered by effective tools to investigate and manipulate plant genomes and proteomes to observe impacts on plant biology. For example, ~20% of plant genes are “lethal” when mutated, precluding detailed development/trait analysis, while many more have such profound effects on plant growth that understanding the underlying biology is almost impossible. Many plants are also polyploid, meaning that genetic ablation and characterisation of even a non-lethal gene is time consuming and non-trivial. In addition, the study of many plant species is blocked by an inability to make transgenic organisms, either to introduce new traits or to perform genome editing, gene deletion or other genetic manipulations. In animal fields PROTACs have proved highly effective for targeted degradation of proteins on demand, for a specific window of time, to allow for investigation of any of these scenarios, and many more besides, but their use has not yet translated to the plant field. PROTAC degraders are small, typically bi-functional, molecules that recruit ubiquitin ligases to degrade a specific protein. Based on existing chemistry, pilot work, and expertise at Dundee we propose to develop PROTACs that are effective in plants to enable basic and applied plant science research, and provide a grounding for future plant-specific PROTAC development. Through selection of highly conserved pan-plant ubiquitination systems, we envisage that this technology will be applicable across all plant lineages, greatly reducing costs, accelerating discovery, and democratising research. In the first instance we will develop PROTACs based on the “best in class” BromoTag system to allow for transient destruction of a protein, thereby enabling rapid examination of any protein’s function, at any life stage or in any scenario, in cultivars of a genetically tractable species (e.g., Arabidopsis, tomato, wheat, rice, potato, barley). We also aim to provide the tools and groundwork to quickly generate pan-plant PROTACs once a specific binder of a protein has been identified. This would, for example, enable mobilisation of genes from silent regions of chromosomes, or between species, to speed up beneficial trait analysis or enable transformation of any plant species, including those traditionally considered recalcitrant. This would reimagine and accelerate basic research, by enabling previously impossible experiments and analyses, while totally revolutionising the process of investigating plants and improving potential new crops.