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

نویسندگان

  • Monica Venere
  • Andrew Snyder
  • Omar Zgheib
  • Thanos D Halazonetis
چکیده

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.

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Phosphorylation of ATR-Interacting Protein on Ser 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 interac...

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عنوان ژورنال:
  • Cancer research

دوره 67 13  شماره 

صفحات  -

تاریخ انتشار 2007