Project description
Advanced protein regulation approach holds promise for cancer and ageing research
Ubiquitylation plays a crucial role in regulating cellular proteins through polyubiquitin chains of diverse structures, collectively known as the ubiquitin code. Despite the existence of analytical tools, there are, as yet, no methods to create specific polyubiquitin chains on proteins in cells. Recently, a method was developed to induce polyubiquitylation with M1, K48, and K63 linkages. On the basis of this technology, the ERC-funded UBICODEWRITERS project plans to create new research tools, including custom enzymes for non-canonical linkages and modules for chain editing and effector identification. These tools will be applied to genome maintenance signalling pathways, focusing on cancer, premature ageing defence, and DNA repair.
Objective
Ubiquitylation is an essential posttranslational modification that governs the activities and interactions of cellular proteins. The structural diversity of polyubiquitin chains, collectively called the ubiquitin code, is thought to determine the fate of the modified proteins. Although many analytical and inhibitory ubiquitin-specific reagents exist, we lack the tools to create polyubiquitin chains of defined linkage on a protein of interest in cells to investigate their signalling functions. We recently established a method to induce substrate-specific polyubiquitylation via three major linkages, M1, K48, and K63. Based on this technology, we now propose to develop a new generation of research tools for the scientific community. This will include the identification and design of custom enzymes for assembling the rarer, still poorly characterised non-canonical linkages and a functionalisation with modules for chain editing, branching, and the identification of effectors. In a combination of biochemical, cell biological, and proteomic approaches, we will then apply these tools to major genome maintenance pathways with prominent roles in the defence against disorders such as cancer and premature ageing. Specifically, we will analyse the significance of non-canonical polyubiquitylation in the response to DNA double-strand breaks and the interplay between degradative and non-degradative ubiquitylation in the regulation of essential DNA replication and repair factors. We envision that our research will not only provide new insight into ubiquitin signalling in genome maintenance, but the new technology developed in this project will facilitate future investigations of polyubiquitin chains, their readers, and their writers in other signalling pathways. Situated at the interface between proteostasis and genome maintenance, this project will thus advance our understanding of two essential cellular surveillance systems with critical functions in human health and well-being.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesgeneticsgenomes
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
55128 Mainz
Germany