Maintenance of genomic stability is essential for cellular homeostasis and prevention of cell death or neoplastic transformation. The DNA of all organisms is constantly under attack by DNA damaging agents, both environmental ones and intracellular metabolic by-products. It is estimated that thousands of DNA lesions are induced in each cell in our body every day, mainly by oxygen radicals. Thus, the DNA damage response is central to maintenance of genomic stability.
The DNA damage response is a complex network of processes and pathways that is activated immediately following damage to the DNA. One of the most potent activators of this system is the double strand break (DSB) – the most cytotoxic DNA lesion, caused by ionizing radiation and radiomimetic chemicals. Two major arms of the DNA damage response are DNA repair systems, and cell cycle checkpoints that temporarily arrest cell cycle progression while the damage is being assessed and repaired. The DNA damage response concludes with cell survival and resumption of normal cellular life cycle, or with programmed cell death, which is probably activated in the face of excessive or irreparable damage.
Genetic defects in the DNA damage response lead to genomic instability syndromes, which usually include tissue degeneration, cancer predisposition, and sensitivity to specific DNA damaging agents. A prototype genomic instability syndrome is ataxia-telangiectasia (A-T). A-T is characterized by neuronal degeneration, immunodeficiency, chromosomal instability, sensitivity to ionizing radiation, and cancer predisposition. Our lab has been investigating A-T since its establishment in 1985. In 1995 we identified the responsible gene, ATM (A-T, Mutated), after intensive positional cloning, and went on to study the catalytic activity of its protein product, ATM. ATM turned out to be a protein kinase that phosphorylates key players in the various branches of the DNA damage response.
Our current research is aimed at a broader understanding of the DNA damage response, with emphasis on the ATM-mediated network. Particular attention is paid to the molecular and physiological basis of A-T, which may eventually lead to new treatment modalities for this disease. Current research directions are:
Identification of novel branches of the ATM-mediated DNA damage response
Investigation of the activation and deactivation of the DNA damage response
Investigation of the interface between the ubiquitin system and the DNA damage response
Investigation of the ATM-mediated DNA damage response in neurons
Obtaining a global view of the DNA damage response using systems
biology tools