Expression of BRC Repeats in Breast Cancer Cells Disrupts the BRCA2-Rad51 Complex and Leads to Radiation Hypersensitivity and Loss of G2/M Checkpoint Control
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BRCA2 is a breast tumor suppressor with a potential function in the cellular response to DNA damage. BRCA2 binds to Rad51 through its BRC repeats. In support of the biological significance of this interaction, we found that the complex of BRCA2 and Rad51 in breast cancer MCF-7 cells was diminished upon conditional expression of a wild-type, but not a mutated, BRC4 repeat using the tetracycline-inducible system. Cells expressing a wild-type BRC4 repeat showed hypersensitivity to gamma-irradiation, an inability to form Rad51 radiation-induced foci, and a failure of radiation-induced G(2)/M, but not G(1)/S, checkpoint control. These results strongly suggest that the interaction between BRCA2 and Rad51 mediated by BRC repeats is critical for the cellular response to DNA damage.
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H-bond staples are not unique to MAPKAPK docking regions bound to MAPKs and are also used in other linear motif based interaction systems such as TGFβ signaling and DNA repair regulation.
“H-bond staples, however, are not unique to MAPKAPK docking regions bound to MAPKs and are also used in other linear motif based interaction systems such as those operating in TGFβ signaling (the TGFβ effector SMAD3 interacts with a linear motif in the adaptor SARA) or in DNA repair regulation (the DNA recombinase RAD51 interacts with a short peptide segment from the scaffold protein BRCA2 ) (39-41”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [40]
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References 35 · Cited by 207
Research works printed but not linked: 8
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- Authors
- Chen, C.-F., Chen, P.-L., Zhong, Q., Sharp, Z. D., & Lee, W.-H.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Lee, Wen-Hwa
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-11
- Volume
- 274
- Issue
- 46
- Pages
- 32931-32935
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1989802855
- Cited by
- 207
- References
- 35
- Citations by year
- 2026: 7 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 4 · 2019: 2 · 2018: 6 · 2017: 2 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 9 · 2012: 7
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Susan G. Komen for the Cure
- National Cancer Institute (CA 58183, P01CA030195, CA-30195, P50CA058183)
- 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 › PARP inhibition in cancer therapy
- Keywords
- BRCA2, RAD51, BRC repeats, breast cancer, MCF-7 cells, radiation hypersensitivity, gamma irradiation, DNA damage response, G2/M checkpoint, RAD51 foci, tetracycline-inducible expression
- MeSH terms
- Amino Acid Sequence, Breast Neoplasms, Cell Cycle, Clone Cells, DNA Damage, DNA-Binding Proteins, Gamma Rays, Humans, Luminescent Proteins, Microscopy, Fluorescence, Mitosis, Molecular Sequence Data, Mutation, Neoplasm Proteins, Protein Binding, Repetitive Sequences, Nucleic Acid, Tetracycline, Transcription Factors, Tumor Cells, Cultured, G2 Phase, S Phase, BRCA2 Protein, Green Fluorescent Proteins, Rad51 Recombinase
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