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 γ-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (γ-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 Met 1775 → Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.
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CTIP and ABRA1/Abraxas contain phospho-SXXF motifs that mediate direct interaction with BRCA1-BRCTs.
“In addition to FANCJ, several proteins, including CTIP and ABRA1/Abraxas, have phospho-SXXF motifs (S is serine, F is phenylalanine and X varies) that mediate the direct interaction with the BRCA1-BRCTs, which are phospho-binding motifs [37–40].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [40]
The C-terminal BRCT domains of BRCA1 form a phospho-peptide recognition domain that specifically binds phospho-peptides containing a pSPxF motif.
“The C-terminal BRCT domains of BRCA1 constitute a phospho-peptide recognition domain that binds specifically to phospho-peptides containing a pSPxF (phosphor-serine-proline-x-phenylalanine) motif (Manke et al., 2003; Rodriguez et al., 2003; Yu et al., 2003).”
From The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression (2014) · cites this paper as Manke et al., 2003
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- Authors
- Manke, I. A., Lowery, D. M., Nguyen, A., & Yaffe, M. B.
- Affiliations
- Massachusetts Institute of Technology (US)
- ORCID
- Yaffe, Michael B.
- Venue
- Science
- Published
- 2003-10-24
- Volume
- 302
- Issue
- 5645
- Pages
- 636-639
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2038260399
- Cited by
- 651
- References
- 23
- Citations by year
- 2026: 13 · 2025: 6 · 2024: 17 · 2023: 25 · 2022: 15 · 2021: 19 · 2020: 24 · 2019: 14 · 2018: 12 · 2017: 15 · 2016: 17 · 2015: 21 · 2014: 29 · 2013: 28 · 2012: 40
- FWCI
- 18.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM-60594, R01GM060594)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BRCT domain, phosphopeptide binding, PTIP, BRCA1, ATM kinase, ATR kinase, DNA damage response, signal transduction, 53BP1 foci, γH2AX, protein localization, breast cancer predisposition, ovarian cancer predisposition, gamma irradiation
- MeSH terms
- Caffeine, Calorimetry, Carrier Proteins, Cell Nucleus, Cytosol, DNA Damage, DNA-Binding Proteins, Gamma Rays, Humans, Nuclear Proteins, Phosphopeptides, Phosphorylation, Phosphoserine, Phosphothreonine, Protein Binding, Tumor Cells, Cultured, Signal Transduction, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Cell Cycle Proteins, Peptide Library, BRCA1 Protein, Amino Acid Motifs, Tumor Suppressor Proteins, Proteomics, Ataxia Telangiectasia Mutated Proteins
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