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Vol. 15, No. 14, pp. 1833-1844, July 15, 2001
1 Department of Genetics, Howard Hughes Medical Institute,
and 2 Department of Medicine, Duke University Medical Center,
Durham, North Carolina 27710, USA
Previous work has established a role for p53 in triggering apoptosis
in response to DNA damage; p53 also induces apoptosis in response to
deregulation of the Rb cell cycle pathway. The latter event is
consistent with a role for the Rb-regulated E2F1 protein as a specific
inducer of apoptosis and p53 accumulation. We now show that DNA damage
leads to a specific induction of E2F1 accumulation, dependent on ATM
kinase activity and that the specificity of E2F1 induction reflects a
specificity in the phosphorylation of E2F1 by ATM as well as the
related kinase ATR. We identify a site for ATM/ATR phosphorylation in
the amino terminus of E2F1 and we show that this site is required for
ATM-mediated stabilization of E2F1. Finally, we also show that E2F1 is
required for DNA damaged induced apoptosis in mouse thymocytes. We
conclude that the cellular response to DNA damage makes use of signals
from the Rb/E2F cell cycle pathway.
[Key Words: E2F1; DNA damage; ATM; ATR; p53; apoptosis]
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