The BRCT Domain Is a Phospho-Protein Binding Domain
Abstract
The carboxyl-terminal domain (BRCT) of the Breast Cancer Gene 1 (BRCA1) protein is an evolutionarily conserved module that exists in a large number of proteins from prokaryotes to eukaryotes. Although most BRCT domain–containing proteins participate in DNA-damage checkpoint or DNA-repair pathways, or both, the function of the BRCT domain is not fully understood. We show that the BRCA1 BRCT domain directly interacts with phosphorylated BRCA1-Associated Carboxyl-terminal Helicase (BACH1). This specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage–induced checkpoint control during the transition from G 2 to M phase of the cell cycle. Further, we show that two other BRCT domains interact with their respective physiological partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phospho-peptides rather than nonphosphorylated control peptides. These data imply that the BRCT domain is a phospho-protein binding domain involved in cell cycle control.
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FANCJ directly and functionally interacts with the BRCA1 gene product.
“This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1.”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [37]
BRCA1-BRCTs directly interact with FANCJ in a manner dependent on FANCJ phosphorylation at S990.
“Since the cloning of FANCJ, it was confirmed that the BRCA1-BRCTs mediate a direct interaction with FANCJ that is dependent on FANCJ phosphorylation at S990 [37].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [37]
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 [37]
The C-terminus contains the phospho-SXXF motif at residues 990-993, which is required for BRCA1 binding.
“Outside the helicase domain, the C-terminus harbors the phospho-SXXF motif (residues 990–993) required for BRCA1 binding (Figure 2) [37].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [37]
The BRCA1-FANCJ interaction depends on phosphorylation of FANCJ serine 990.
“The BRCA1– FANCJ interaction was dependent upon phosphorylation of the FANCJ residue serine 990 [37].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [37]
BRCA1 binding to FANCJ is essential for checkpoint control during the G2-M phase of the cell cycle.
“Initially, it was determined that BRCA1 binding to FANCJ was essential for checkpoint control during the G2–M phase of the cell cycle [37].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [37]
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- Authors
- Yu, X., Chini, C. C. S., He, M., Mer, G., & Chen, J.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Chen, Junjie
- Venue
- Science
- Published
- 2003-10-24
- Volume
- 302
- Issue
- 5645
- Pages
- 639-642
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2024131694
- Cited by
- 862
- References
- 15
- Citations by year
- 2026: 19 · 2025: 8 · 2024: 23 · 2023: 51 · 2022: 30 · 2021: 33 · 2020: 36 · 2019: 23 · 2018: 19 · 2017: 16 · 2016: 27 · 2015: 37 · 2014: 36 · 2013: 37 · 2012: 60
- FWCI
- 20.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA089239, CA89239, R01CA092312, CA92312)
- 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, BRCA1, BACH1, DNA damage checkpoint, G2/M transition, cell cycle regulation, phosphopeptide binding, DNA repair
- MeSH terms
- Carrier Proteins, Cell Cycle, Cell Line, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Mitosis, Mutation, Nuclear Proteins, Phosphoprotein Phosphatases, Phosphoproteins, Phosphorylation, Phosphoserine, Protein Binding, Recombinant Fusion Proteins, RNA Polymerase II, Transcription Factors, Transfection, Tumor Cells, Cultured, G2 Phase, Protein Structure, Tertiary, Cell Cycle Proteins, Peptide Library, BRCA1 Protein, RNA Helicases, Amino Acid Motifs, RNA, Small Interfering, E2F Transcription Factors, Fanconi Anemia Complementation Group Proteins
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