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p73 Regulation by Chk1 in Response to DNA Damage

Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021,¹ Department of Biological Sciences, Columbia University, New York, New York 10027²

Received 1 April 2003/ Returned for modification 5 June 2003/ Accepted 6 August 2003

The checkpoint kinase 1 (Chk1) is an essential component of the DNA damage checkpoint. Previous studies have demonstrated an indispensable role for the p53-related transcription factor p73 in DNA damage-induced apoptosis. Here, we provide evidence that p73 is a target of Chk1. We found that endogenous p73 is serine phosphorylated by endogenous Chk1 upon DNA damage, which is a mechanism required for the apoptotic-inducing function of p73. Consistent with this, we discovered that endogenous p73 interacts with Chk1 and is phosphorylated by Chk1 at serine 47 in vitro and in vivo. In contrast, Chk2 does not phosphorylate p73 in vitro. Moreover, mutation of serine 47 abolishes both Chk1-dependent phosphorylation of p73 upon DNA damage in vivo and the ability of Chk1 to upregulate the transactivation capacity of p73. Our data indicate a novel biochemical pathway through which the p73 proapoptotic function requires DNA damage-triggered p73 phosphorylation by Chk1.

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