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Phosphorylation of ATR-Interacting Protein on Ser²³⁹ Mediates an Interaction with Breast-Ovarian Cancer Susceptibility 1 and Checkpoint Function

¹ The Wistar Institute; Programs in ² Cell and Molecular Biology and ³ Biochemistry, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania; and ⁴ Departments of Molecular Biology and Biochemistry, University of Geneva, Geneva, Switzerland

Requests for reprints: Thanos D. Halazonetis, Department of Molecular Biology, University of Geneva, CH-1211, Geneva 4, Switzerland. Phone: 41-22-379-61-12; Fax: 41-22-379-68-68; E-mail: thanos.halazonetis{at}molbio.unige.ch.

The signaling of DNA damage and replication stress involves a multitude of proteins, including the kinases ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR), and proteins with BRCA1 COOH-terminal (BRCT) domains. The BRCT domain–containing proteins facilitate the phosphorylation of ATM/ATR substrates and can be coimmunoprecipitated with ATM or ATR. However, their mode of interaction with the ATM/ATR kinases remains elusive. Here, we show that breast-ovarian cancer susceptibility 1 (BRCA1) interacts directly with ATR-interacting protein (ATRIP), an obligate partner of ATR. The interaction involves the BRCT domains of BRCA1 and Ser²³⁹ of ATRIP, a residue that is phosphorylated in both irradiated and nonirradiated cells. Consistent with a role of BRCA1 in ATR signaling, substitution of Ser²³⁹ of ATRIP with Ala leads to a G₂-M checkpoint defect. We propose that a direct physical interaction between BRCA1 and ATRIP is required for the checkpoint function of ATR. [Cancer Res 2007;67(13):6100–5]

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