Ataxia telangiectasia mutated (ATM) is essential for the maintenance of genomic stability. ATM is a 370 kDa serine-threonine kinase that is constitutively expressed in various tissues. Although primarily nuclear, ATM is also found at lower levels associated with cytoplasmic vesicles. As a PI 3-kinase family member, ATM is able to phosphorylate a wide variety of substrates including proteins involved in sensing and repairing DNA damage such as p53 and Brca1 (2). Normally ATM is found as an inactive homodimer. Following ionizing radiation ATM undergoes autophosphorylation and dissociates into catalytically active monomers. Phospho-specific ATM antibodies have aided in the identification of autophosphorylation sites and their roles in the DNA damage response (3). Examination of ATM localization by immunofluorescence using a general ATM antibody has demonstrated an association with sites of DNA double-strand breaks along with the histone gamma-H2AX (4). This observation is consistent with a role in the early detection of DNA damage. In addition to DNA repair, ATM is also important for normal cell cycle progression. ATM mediates checkpoint signaling during the cell cycle to ensure the fidelity of DNA replication and induce arrest or apoptosis when necessary (5). The ATM mediated DNA damage response may provide a strategy for sensitizing cancer cells to radiotherapy. However this may be a problem in patients with ATM deficiencies. This possibility was examined by the Clarke group by looking at patients with mutations in ATM (6). The authors looked at ATM levels in breast cancer patients with clinical radiosensitivity through qPCR and through western blotting with the ATM antibody. They found patients with about 50% of normal ATM levels were at high risk for clinical radiosensitivity (6). Guo et al. characterized additional ATM functions in response to oxidative stress (7). Their study used the ATM antibody to show activation of ATM following exposure to hydrogen peroxide proceeds through an alternative mechanism by inducing ATM dimerization through disulfide bond formation (7). Our growing knowledge of DNA damage repair has helped us to understand genomic integrity in normal cells and devise strategies for efficiently killing cancer cells. The Ouchi group at Northwestern University identified additional factors regulating the DNA damage response that help to further characterize this complex and important pathway (8). They used the ATM antibody to monitor activation of the DNA damage response and identified intercellular contact through adherens junctions as an important regulator of apoptosis the DNA damage response (8). This study demonstrated the importance of the cellular microenvironment in determining the cell’s response to DNA damage.
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