DNA damage elicits a cellular program of damage control coordinated by the kinase activity of ATM. Kirshner et al. show that ATM activity, but not abundance, is severely compromised in murine cells in which the Tgfβ1 gene is deleted and in human epithelial cells in which TGFβ signaling is blocked. This defect is evident by the absence of γH2AX foci at 30 min after exposure to ionizing radiation (2 Gy) in Tgfβ1-null compared to Tgfβ1-heterozygote keratinocytes, as detected by γH2AX immunofluorescence (green) in DAPI-stained nuclei (blue). As a consequence of the failure of ATM to phosphorylate its substrates, inhibiting TGFβ signaling compromises radiation-induced apoptosis and cell-cycle arrest and increases cell kill as measured by clonogenic assay. These data demonstrate a previously unsuspected role for extracellular signaling in the genotoxic stress program of epithelial cells, and contributes a new and important action for TGFβ1 as a tumor suppressor. Future studies to identify the molecular mechanism of ATM kinase inhibition in epithelial cells may support the use of TGFβ inhibitors to increase response to radiotherapy. For details, see the article by Kirshner et al. on page 10861 of this issue.

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