ONIDDAC

Oncogene-Induced DNA Damage in Cancer

Coordinatore	UNIVERSITE DE GENEVE    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Switzerland [CH]
Totale costo	2˙499˙351 €
EC contributo	2˙499˙351 €
Programma	FP7-IDEAS-ERC Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	ERC-2011-ADG_20110310
Funding Scheme	ERC-AG
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-05-01   -   2017-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITE DE GENEVE  Organization address address: Rue du General Dufour 24 city: GENEVE postcode: 1211 contact info Titolo: Dr. Nome: Alex Cognome: Waehry Email: send email Telefono: +41 22 379 75 60 Fax: +41 22 379 11 80	CH (GENEVE)	hostInstitution	2˙499˙351.00
2	UNIVERSITE DE GENEVE  Organization address address: Rue du General Dufour 24 city: GENEVE postcode: 1211 contact info Titolo: Prof. Nome: Athanassios Dimitrios (Thanos) Cognome: Halazonetis Email: send email Telefono: +41 22 379 6112 Fax: +41 22 379 68 68	CH (GENEVE)	hostInstitution	2˙499˙351.00

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 Obiettivo del progetto (Objective)

'I recently proposed a model that helps explain the presence of p53 mutations and genomic instability in human cancers (Nature, 2005; Nature 2006; Science 2008). The key features of this model are that oncogenes induce DNA replication stress, which in turn leads to DNA double-strand breaks, genomic instability and p53-induced senescence or apoptosis. This model is relevant for almost all cancer types and explains the spectrum of mutations being reported in thousands of human cancers by the cancer sequencing consortia. In this project, I propose to take the next logical steps that follow from my discovery. Specifically, I propose the following objectives: 1. Elucidate the mechanisms by which oncogenes induce DNA replication stress. Oncogene-induced genomic deletions map within very large actively transcribed genes. Accordingly, I hypothesize that oncogenes and transcription synergistically disrupt pre-replicative complexes resulting in large genomic regions that have a low density of replication initiation events. To test this hypothesis, I propose to introduce by site-directed homologous recombination a transcription termination sequence at the beginning of very large gene and determine whether it remains sensitive to oncogene-induced genomic instability. Genome-wide transcription and DNA replication patterns will also be examined in cells that are sensitive to oncogene-induced DNA replication stress (most somatic cells and cell lines) and cells that are resistant (induced pluripotent stem cells). 2. Identify and characterize genes necessary for proliferation of cells with oncogene-induced DNA replication stress. Using high throughput siRNA screens we will identify genes, whose depletion inhibits proliferation of cells with oncogene-induced DNA replication stress, without affecting normal cells. We will explore the function of these genes using molecular biology, structural biology and genetic approaches. Some promising candidates have already been identified.'