“We now understand the chain of events that leads to instantaneous activation of the enormous cellular response to DNA lesions”

This paper is a review, and reviews tend to be highly cited. But there is probably more to it than that. The paper deals with a central subject in biomedical research: the cellular responses to DNA damage. These responses are essential for maintaining the genomic stability and integrity essential for preventing cellular death or malignant transformation. Defects in this system lead to a variety of very severe diseases. Thus, this field is of great interest to basic scientists as well as to clinicians from many areas of medicine.

My involvement in this field stems from my long-term interest in a devastating human genetic disorder called ataxia-telangiectasia (A-T), an interest that began when I was a graduate student some 27 years ago and met a family with A-T. The striking phenotype of the patients led me to make the disease the subject of my Ph.D. thesis and I have remained in A-T research ever since. A-T is caused by a defect in the cellular response to a specific type of DNA lesion—the double-strand break. This is the most critical DNA lesion caused by ionizing radiation. A-T patients suffer from neurodegeneration, immunodeficiency, radiation sensitivity, genomic instability, and cancer predisposition. In 1995, our lab in Tel Aviv identified the defective gene that leads to A-T, and called it ATM (A-T, Mutated). We then shifted gears from molecular genetics to protein chemistry and began studying the ATM protein, the product of the ATM gene, in order to understand the physiological basis of A-T. Work in our lab and many other labs has elucidated the role of the ATM protein as the chief regulator and mobilizer of the cellular responses to DNA double-strand breaks. We now understand how one protein, ATM, can stir such a wide chain of reactions, sometimes in response to very few or even a single double-strand break in the DNA!