PROTEUS

Proteomic investigations of ubiquitin signals in DNA repair and chromatin organization

Coordinatore	INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH    more  Organization address address: ACKERMANNWEG 4 city: MAINZ postcode: 55128 contact info Titolo: Mrs Nome: Franziska Cognome: Hornig Email: send email Telefono: +49 61313921453 Fax: +49 61313921421
Nazionalità Coordinatore	Germany [DE]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-03-01   -   2018-02-28

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH  Organization address address: ACKERMANNWEG 4 city: MAINZ postcode: 55128 contact info Titolo: Mrs Nome: Franziska Cognome: Hornig Email: send email Telefono: +49 61313921453 Fax: +49 61313921421	DE (MAINZ)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Genome integrity is constantly challenged by endogenous and environmental factors that can induce different types of DNA lesions. Failure to repair DNA lesions can lead to genomic instability and contribute to human diseases such as cancer and premature ageing. To counteract these potentially devastating effects caused by DNA damage, eukaryotic cells have evolved complex DNA repair pathways. Protein ubiquitylation has emerged as an important regulatory mechanism of the cellular response to DNA damage: Ubiquitin-modifying enzymes are recruited to sites of DNA damage and are essential for the repair of DNA lesions. However, for most of these enzymes the protein substrates that are modified in response to DNA damage and the molecular functions in DNA damage signalling remain obscure. Recent advances in mass spectrometry as well as novel methods for the enrichment of ubiquitylated peptides permit to systematically study protein ubiquitylation after cellular perturbations. In the proposed research project we plan to perform a quantitative analysis of protein ubiquitylation in ubiquitin ligase knockdown cells to identify the physiological substrates of ubiquitin ligases that function in DNA repair and chromatin organization. To this end, the cellular expression of selected ubiquitin ligases, including RAD18, BRCA1/BARD1, RNF20/40 and RING1A/RING1B/BMI1, will be downregulated by transient transfection of siRNA. Wildtype and knockdown cells will be treated with DNA damage-inducing agents and the ubiquitylation patterns in these cells will be comparatively analyzed using quantitative mass spectrometry. Biochemical and cell biological methods will be employed to characterize the physiological relevance of the site-specific protein ubiquitylation for the target proteins. These investigations are expected to uncover ubiquitin ligase – substrate relations and to deepen the understanding of the regulatory roles of ubiquitin ligases in processes that maintain chromatin integrity.'