Abstract |
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.
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Authors | Isaac A Manke, Drew M Lowery, Anhco Nguyen, Michael B Yaffe |
Journal | Science (New York, N.Y.)
(Science)
Vol. 302
Issue 5645
Pg. 636-9
(Oct 24 2003)
ISSN: 1095-9203 [Electronic] United States |
PMID | 14576432
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- BRCA1 Protein
- Carrier Proteins
- Cell Cycle Proteins
- DNA-Binding Proteins
- Nuclear Proteins
- PAXIP1 protein, human
- Peptide Library
- Phosphopeptides
- Tumor Suppressor Proteins
- Phosphothreonine
- Phosphoserine
- Caffeine
- Atr protein, mouse
- ATM protein, human
- ATR protein, human
- Ataxia Telangiectasia Mutated Proteins
- Atm protein, mouse
- Protein Serine-Threonine Kinases
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Topics |
- Amino Acid Motifs
- Ataxia Telangiectasia Mutated Proteins
- BRCA1 Protein
(chemistry, metabolism)
- Caffeine
(pharmacology)
- Calorimetry
- Carrier Proteins
(chemistry, metabolism)
- Cell Cycle Proteins
(antagonists & inhibitors, metabolism)
- Cell Nucleus
(metabolism)
- Cytosol
(metabolism)
- DNA Damage
- DNA-Binding Proteins
- Gamma Rays
- Humans
- Nuclear Proteins
(chemistry, metabolism)
- Peptide Library
- Phosphopeptides
(metabolism)
- Phosphorylation
- Phosphoserine
(metabolism)
- Phosphothreonine
(metabolism)
- Protein Binding
- Protein Serine-Threonine Kinases
(antagonists & inhibitors, metabolism)
- Protein Structure, Tertiary
- Proteomics
- Signal Transduction
- Tumor Cells, Cultured
- Tumor Suppressor Proteins
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