Molecular Bases of Ataxia Telangiectasia: One Kinase Multiple Functions

Ataxia Telangiectasia (A-T) is an autosomal recessive hereditary progressive neurodegener‐ ative and multisystem disease characterized by cerebellar ataxia, telangiectasia, recurrent si‐ nopulmonary infections, variable immunologic defects among which a significantly higher incidence of leukaemia and lymphoma and type 2 diabete. This disorder has been clearly linked to the loss of expression of the serine/threonine kinase ATM (Ataxia Telangiectasia Mutated), a central player of the DNA Damage Response (DDR). Several clinical features of A-T patients, as well as the pleiotropic phenotypes observed in Atm deficient mice, can be associated to a defective DDR. Moreover, ATM deficient cellular models display radiosensi‐ tivity and failure to activate cell cycle checkpoints in response to DNA damaging agents. Emerging evidences indicate that ATM kinase may be involved in several additional signal‐ ling pathways, among which the signalling cascades triggered by oxidative stress, hypoxia, autophagy, metabolic changes, growth factors and death receptors, suggesting that the en‐ dangerment of these functions in the absence of ATM activity may importantly contribute to the development of A-T pathology.