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

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.
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.)
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
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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