Phosphorylation of ATR-interacting protein on Ser239 mediates an interaction with breast-ovarian cancer susceptibility 1 and checkpoint function.

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 Ser(239) of ATRIP, a residue that is phosphorylated in both irradiated and nonirradiated cells. Consistent with a role of BRCA1 in ATR signaling, substitution of Ser(239) of ATRIP with Ala leads to a G(2)-M checkpoint defect. We propose that a direct physical interaction between BRCA1 and ATRIP is required for the checkpoint function of ATR.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, BRCA1 Protein, Breast Neoplasms, Cell Cycle Proteins, DNA Damage, DNA-Binding Proteins, Exodeoxyribonucleases, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Humans, Molecular Sequence Data, Ovarian Neoplasms, Phosphoproteins, Phosphorylation, Protein-Serine-Threonine Kinases, Sequence Homology, Amino Acid, Serine
Cancer Res.
Date: Jul. 01, 2007
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