Our lab investigates the human genetic disorder ataxia-telangiectasia (A-T). A-T is initially manifested as ataxia (lack of coordination of movements) during childhood, which later develops into severe neuromotor dysfunction. This results from progressive degeneration of the cerebellar cortex, manifested as striking loss of the Purkinje and granule cells. Telangiectasias (dilated blood vessels) appear later, usually in the eyeballs. This multisystem disorder also includes immunodeficiency, chromosomal instability, cancer predisposition, and acute sensitivity to agents that induce double-strand breaks in the DNA, such as ionizing radiation (IR) and radiomimetic chemicals.
The gene that is mutated in A-T, called ATM, was identified and named in our lab in 1995. Its product, the ATM protein, is a powerful and versatile protein kinase, which is involved in various aspects of cellular homeostasis and is most vigorously activated in the presence of DNA double-strand breaks. It then mobilizes a vast signaling network known as the DNA damage response - by phosphorylating numerous key players in its multiple branches. ATM also enhances the responses to other DNA lesions or abnormal DNA structures by phosphorylating pertinent proteins.
Our lab investigates the various branches of the ATM-mediated DNA damage response. We strive to understand how the loss of ATM impacts the cell’s complex response to genotoxic stresses, and to explain the most cardinal and debilitating symptom of A-T – the cerebellar degeneration.