BRCT repeats as phosphopeptide-binding modules involved in protein targeting.

We used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. Using a library of partially degenerate phosphopeptides, we identified tandem BRCT (BRCA1 carboxyl-terminal) domains in PTIP (Pax transactivation domain-interacting protein) and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize ...
substrates phosphorylated by the kinases ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia- and RAD3-related) in response to gamma-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (gamma-H2AX)-containing nuclear foci, a marker of DNA damage. These findings provide a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation Met1775 --> Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.
Mesh Terms:
Amino Acid Motifs, BRCA1 Protein, Caffeine, Calorimetry, Carrier Proteins, Cell Cycle Proteins, Cell Nucleus, Cytosol, DNA Damage, DNA-Binding Proteins, Gamma Rays, Humans, Nuclear Proteins, Peptide Library, Phosphopeptides, Phosphorylation, Phosphoserine, Phosphothreonine, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proteomics, Signal Transduction, Tumor Cells, Cultured, Tumor Suppressor Proteins
Date: Oct. 24, 2003
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