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 natural sciencesbiological sciencesgeneticsDNA Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2012-CIG - Marie-Curie Action: "Career Integration Grants" Call for proposal FP7-PEOPLE-2012-CIG See other projects for this call Funding Scheme MC-CIG - Support for training and career development of researcher (CIG) Coordinator CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH Address Lazarettgasse 14 akh bt 25.3 1090 Wien Austria See on map Region Ostösterreich Wien Wien Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Administrative Contact Sigrid Strodl (Ms.) Links Contact the organisation Opens in new window Website Opens in new window EU contribution No data
