NONCANATM · DNA damage response: ATMIN regulated non-canonical ATM activation

DNA damage response: ATMIN regulated non-canonical ATM activation

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 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 this proposal have the aim to understand the molecular basis of this pathway. During the four years of this project we have shown that ATMIN is an important ATM cofactor following replications stress. Under such stress conditions ATMIN is required for ATM activity in order to recruit DNA repair proteins to sites of damage (Schmidt et al, 2014). Furthermore, we have investigated the molecular identity of the non-canonical ATM signaling pathway by taking a global, unbiased proteomic approach. This approach allowed us to identify the proteins that are phosphorylated in an ATMIN-ATM dependent and independent manner upon replication stress (Mazouzi et al, 2016). In parallel, we have established a genetic murine model that allowed us to dissect the contribution of ATMIN and NBS to ATM activation in T cells. This model allowed us to draw the conclusion that ATMIN has both synergistic and independent functions in T cells with regard to NBS (Prochazkova at al, 2016). In summary, our research has established the importance of the ATMIN-ATM signaling pathway in stress conditions, such as replication stress, and moreover has highlighted the role of this pathway in the development of lymphoid T cells.

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