Objective
The checkpoint kinase ATM (Ataxia Telangiectasia Mutated) transduces genomic stress signals to halt cell cycle progression and promote DNA repair in response to DNA damage. ATMIN (for ATM INteractor) is a cofactor for ATM that shares functional homologies with another cofactor, NBS1. Whereas NBS1 is required for ATM function after induction of double-stand breaks (DSBs), ATMIN is essential for ATM signaling triggered by agents that induce ‘chromatin changes’ (including chloroquine and osmotic stress). However, the significance of this non-canonical mode of ATM signaling has been unclear.
My recent work has shown that the ATMIN/ATM signaling pathway is crucial for the function of the ATM kinase, and hence the maintenance of genomic integrity and tumour suppression. In order to determine whether ATMIN is required for any of the physiological functions of ATM, we generated a conditional knock-out mouse model for ATMIN in B cells. ATM signaling was dramatically reduced following osmotic stress in ATMIN-mutant B cells. As a consequence, ATMIN deficiency led to impaired class switch recombination, and subsequently ATMIN-mutant mice developed B cell lymphomas. Thus, somewhat surprisingly given the large body of evidence supporting a role for NBS1 in ATM activation, ablation of ATMIN-dependent ATM activation leads to a severe defect in ATM function. Thus this data strongly argues for the existence of a second independent mode of ATM activation that contributes to ATM function. The molecular trigger (which can be mimicked by osmotic stress) and the components of this second ATMIN-dependent arm of the ATM pathway are unknown, but my data clearly show that it is physiologically relevant.
It is worth noting that while a large amount of scientific effort has gone into characterising ATM signaling triggered by DSBs, very little is known about non-canonical ATM signaling. The experiments outlined in my research plan have the aim to understand the molecular basis of this pathway.
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: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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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.
FP7-PEOPLE-2012-CIG
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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.
MC-CIG - Support for training and career development of researcher (CIG)
Coordinator
1090 Wien
Austria
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.