UBIQUITIN CONTROL OF GENOME STABILITY
Our research focuses on the role of ubiquitin and ubiquitin-like modifiers in the regulation of genome stability. We aim to understand how cells exploit the ubiquitin and ubiquitin-like systems to react to harmful conditions – genotoxic stress, inflammation, viral infection – and how these signals are further decoded into functional outputs.
Ubiquitin conjugation is a widely-used protein modification that regulates virtually all cellular pathways, including those relevant for cancer cell proliferation and genome integrity such as the DNA damage response (DDR) and DNA replication. Ubiquitin is covalently conjugated to lysine (K) residues on target protein by a multistep process, leading to the formation of different polyubiquitin chains that result in a multitude of functional outcomes, including both proteolytic and non-proteolytic activities. A paradigmatic example of the non-proteolytic role of ubiquitin is represented by the DDR signalling pathway activated by DNA double strand breaks, which is initiated by the apical kinase ATM (ataxia-telangiectasia mutated). ATM-dependent phosphorylation events are rapidly followed by chromatin ubiquitination on histone H2As, mediated by the E3 ligases RNF8 and RNF168. Ubiquitinated H2As represent the docking site for downstream factors, such as 53BP1 and the BRCA1 complex, which are required for promoting DNA repair. The key role of RNF168 has been further demonstrated by the identification of RNF168 gene mutations leading to a disorder called RIDDLE syndrome which is characterized by radiosensitivity, immunodeficiency and cancer predisposition, clearly identifying this ubiquitin-mediated pathway as a potential therapeutic target. Indeed, the ubiquitin system is particularly attractive as new anticancer target, thanks to the presence of specific enzymatic – and therefore "druggable" – activities modulating different cellular pathways. Inhibiting key ubiquitin-related DNA repair factors could potentiate commonly used anticancer drugs that induce genotoxic stress. However, reaching this goal requires mechanistic understanding of ubiquitin-mediated control of genome stability, beyond the few molecular events known to date.
Prizes and Awards
1. Charles Rodolphe Brupbacher AWARD for YOUNG INVESTIGATOR – to Maria Chiara Raso for the project: “Deregulated Interferon-stimulated gene 15 (ISG15) leads to DNA replication stress and genomic instability”
The Charles Rodolphe Brupbacher Foundation awards prizes to young scientists every two years. The winners will be nominated from the circle of authors who submitted an abstract for the scientific symposium
2. IDA DE POTTÈRE-LEUPOLD AND DR. IUR. ERIK DE POTTÈRE CANCER RESEARCH AWARD – Comprehensive Cancer Center Zurich – to Jonas Schmid for the project: “Histone ubiquitination by the DNA damage response is required for efficient DNA replication in unperturbed S phase”
The award recognizes doctoral students and early-career scientists and physician-scientists of the Comprehensive Cancer Center Zurich, who have made a significant contribution to basic and/or clinical cancer research