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Science 302 (5645): 636-639

Copyright © 2003 by the American Association for the Advancement of Science

BRCT Repeats As Phosphopeptide-Binding Modules Involved in Protein Targeting

Isaac A. Manke, Drew M. Lowery,* Anhco Nguyen,* Michael B. Yaffe{dagger}

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.

Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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* These authors contributed equallyto this work.

{dagger} To whom correspondence should be addressed. E-mail: myaffe{at}mit.edu


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Y.-S. Tak, Y. Tanaka, S. Endo, Y. Kamimura, and H. Araki (2006)
EMBO J. 25, 1987-1996
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DNA Damage-Induced BARD1 Phosphorylation Is Critical for the Inhibition of Messenger RNA Processing by BRCA1/BARD1 Complex..
H.-S. Kim, H. Li, M. Cevher, A. Parmelee, D. Fonseca, F. E. Kleiman, and S. B. Lee (2006)
Cancer Res. 66, 4561-4565
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