First and foremost, an important and interesting scientific question was being addressed. The activation of the ATM kinase is the first step in cellular responses to ionizing irradiation and other cellular stresses that introduce strand breaks into the DNA. This cellular response has implications for both cancer development as well as cancer therapies. Second, the mechanism that we elucidated for this activation turned out to be an elegant and novel biochemical process. In fact, we are not aware of any other protein kinase whose cellular activity is regulated in the same way that ATM activity is regulated. The ATM kinase cannot access cellular substrates in unperturbed cells because the kinase domain is blocked by the binding of an internal domain of a partner ATM molecule and it is only after DNA damage that the kinase phosphorylates its partner molecule, causing dissociation of the dimer and making the kinase domain accessible to other substrates. Third, we proposed a concept that was rather novel and provocative for the field, namely that the activation of the ATM kinase comes not from binding of the enzyme to DNA breaks directly but rather from changes in higher order nuclear structures that are altered by the introduction of the DNA breaks. Demonstrating ATM activation following cellular treatments that alter nuclear structures without introducing DNA breaks supported this radical notion. Fourth, the generation of a phosphospecific antibody that is a surrogate marker of activated ATM provided a very useful reagent for the field, one that allows many questions to be addressed that were too technically challenging when the only assay for ATM activity was an in vitro kinase assay. Finally, I think that many scientists, particularly those in training, appreciated the paper because of the way that the experiments were designed and the many standard biochemical techniques that were utilized.

As discussed above, several new biologic concepts were generated by the data presented. However, the phosphospecific antibody that specifically binds to ATM when it has become activated following cellular stresses is likely to become a widely-used reagent in cancer biology studies. It is a very sensitive and specific marker of ATM activation and of the exposure of cells to various types of stimuli, ranging from noxious stimuli to normal physiologic processes. It was previously quite difficult to assess this activation, but now it can be done by simple approaches, even in tissues and cell preparations.

Cells in our bodies have developed sophisticated ways to deal with exposure to toxic agents in our environment. In particular, cells must be able to appropriately respond when their DNA has been damaged, either by natural processes such as oxidative stress or by exposure to chemicals or radiation from the environment. If the response to DNA damage is not optimal, the result can be development of cancer or birth defects. In addition, once a cancer has developed, radiation and most chemotherapies that we use damage DNA in order to kill the tumor cells. Thus, understanding how cells respond to DNA damage is critical for understanding both the development of cancer as well as its treatment. This paper identified the very first molecular events that happen in cells as they deal with the type of damage to DNA that occurs following exposure to irradiation or oxidative stresses. In addition to providing reagents as well as an important conceptual basis for future studies of these processes, these discoveries provide tools that allow us to begin to modulate cellular responses to DNA damage with the goals of enhancing DNA repair processes to prevent cancer and reduce toxicities of cancer therapies. In addition, these insights will facilitate development of approaches to make tumors more sensitive to radiation and chemotherapies.

Twelve years ago, my lab first reported the role of the p53 tumor suppressor protein in modulating cellular responses to DNA damage and shortly thereafter linked p53 induction to the ATM gene product. The ATM gene was cloned in 1995 and in 1998 we demonstrated that ATM was a bona fide protein kinase. Over the past few years, we have identified numerous substrates of the ATM kinase, but the mechanisms leading to initiation of cellular ATM kinase activity remained elusive. This paper is one culmination of the natural progress of studying this cellular stress response pathway.

Michael B. Kastan, M.D., Ph.D. 
Professor and Chairman, Department of Hematology-Oncology 
St. Jude Children's Research Hospital
Memphis, TN, USA

Christopher J. Bakkenist, Ph.D.
Postdoctoral Research Associate
Department of Hematology-Oncology
St. Jude Children’s Research Hospital
Memphis, TN, USA