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Molecular and Cellular Biology, November 2003, p. 8161-8171, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8161-8171.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

p73{alpha} Regulation by Chk1 in Response to DNA Damage

Susana Gonzalez,1 Carol Prives,2 and Carlos Cordon-Cardo1*

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{alpha} in DNA damage-induced apoptosis. Here, we provide evidence that p73{alpha} is a target of Chk1. We found that endogenous p73{alpha} is serine phosphorylated by endogenous Chk1 upon DNA damage, which is a mechanism required for the apoptotic-inducing function of p73{alpha}. Consistent with this, we discovered that endogenous p73{alpha} interacts with Chk1 and is phosphorylated by Chk1 at serine 47 in vitro and in vivo. In contrast, Chk2 does not phosphorylate p73{alpha} in vitro. Moreover, mutation of serine 47 abolishes both Chk1-dependent phosphorylation of p73{alpha} upon DNA damage in vivo and the ability of Chk1 to upregulate the transactivation capacity of p73{alpha}. Our data indicate a novel biochemical pathway through which the p73{alpha} proapoptotic function requires DNA damage-triggered p73{alpha} phosphorylation by Chk1.

* Corresponding author. Mailing address: Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021. Phone: (212) 639-7746. Fax: (212) 794-3286. E-mail: cordon-c{at}mskcc.org.

Molecular and Cellular Biology, November 2003, p. 8161-8171, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8161-8171.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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