ROLE OF THE ATAXIA TELANGIECTASIA MUTATED KINASE (ATM) IN THE CONTROL OF PROTEIN UBIQUITINATION AND STABILITY

Ataxia Telangiectasia (AT) is a genetic disease characterized by cerebellar ataxia and immunodeficiency. AT is linked to the loss of function of ATM protein, which normally plays a central function in stress responses upon DNA damage. Recently ATM protein has been shown to be able to modulate the stability of some important effectors of the stress response, mainly trough the phosphorylation of a family of enzymes involved in the control of protein quality and stability. However, the molecular mechanisms through which ATM may modulate protein quality and stability are largely obscure. The control of protein quality and stability is essential for the correct balance between proliferation and cell death and indeed it is severely affected in many pathologies, among which several neurodegenerative disorders, where the loss of this control has been proposed as a leading cause for neuronal cell death. The major aim of this proposal is to perform a wide proteomic approach to identify those proteins whose stability is modulated through ATM-kinase-activity. Proteomic studies will be carried out comparing the panel of proteins targeted for degradation in the presence and in the absence of ATM. This approach will lead to identification of a set of proteins differently degradated in AT cells versus wt cells. Experiments to test the contribution of these events to AT phenotype, perticularly to programmed cell death, will provide new insights on the functional markers of AT and may suggest novel therapeutic targets.