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.
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. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences genetics DNA
- medical and health sciences medical biotechnology cells technologies stem cells
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences molecular biology structural biology
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
ERC-2011-ADG_20110310
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Host institution
1211 Geneve
Switzerland
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.