A Novel Breast Cancer–Associated BRIP1 ( FANCJ/BACH1 ) Germ-line Mutation Impairs Protein Stability and Function
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Abstract
Purpose: BRCA1-interacting protein 1 (BRIP1; FANCJ/BACH1), which encodes a DNA helicase that interacts with BRCA1, has been suggested to be a low-penetrance breast cancer predisposing gene. We aimed to assess whether BRIP1 mutations contribute to breast cancer susceptibility in our population and, if so, to investigate the effect of such mutation(s) on BRIP1 function. Experimental Design: A series of 49 breast/ovarian cancer families, devoid of a BRCA1/BRCA2 mutation, were screened for BRIP1 mutations. Functional analyses, including coimmunoprecipitation and stability assays, were employed to further characterize a previously unreported variant. Results: Five sequence alterations were identified, of which four had been already described. Herein, we report a novel BRIP1 germ-line mutation identified in a woman with early-onset breast cancer. The mutation consists of a 4-nucleotide deletion (c.2992-2995delAAGA) in BRIP1 exon 20 that causes a shift in the reading frame, disrupts the BRCA1-binding domain of BRIP1, and creates a premature stop codon. Functional analysis of the recombinant mutant protein in transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1. Loss of the wild-type BRIP1 allele with retention of the mutated one was observed in the patient's breast tumor tissue. Conclusions: These results, by showing that the newly identified BRIP1 c.2992-2995delAAGA mutation is associated with instability and functional impairment of the encoded protein, provide further evidence of a breast cancer–related role for BRIP1.
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Reduced protein expression was reported for two breast cancer-associated FANCJ mutants, including c.2992-2995delAAGA, which creates a deletion and a premature stop codon after the helicase domain.
“Using this approach, reduced protein expression was reported for two breast cancer-associated FANCJ mutants, including c.2992–2995delAAGA, which generates a deletion and results in a premature stop codon after the helicase domain [43].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [43]
A germline FANCJ mutation, c.2992-2995delAAGA, was identified in a tumor that had lost the corresponding wild-type allele.
“More recently, the idea that FANCJ could act as a classic tumor suppressor was bolstered with the identification of a germline FANCJ mutation, c.2992–2995delAAGA, in which the tumor had lost the corresponding wild-type allele [43].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [43]
Several FANCJ mutations targeting noncoding genomic DNA have been identified in breast cancer and Fanconi anemia patients.
“Along these lines, several FANCJ mutations targeting noncoding genomic DNA have been identified in both breast cancer and FA patients [28,43].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [43]
Tumor suppression likely requires both the helicase domain and nuclear co-localization with BRCA1, because variants in the nuclear localization sequence (A173C) or BRCA1-binding domain were detected in patients with a strong family history of breast cancer.
“Tumor suppression likely requires not only the helicase domain, but also nuclear co-localization with BRCA1, given that variants with a sequence change in the nuclear localization sequence (A173C) [60] or BRCA1-binding domain were detected in patients with a strong family history of breast cancer [43,53].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [43]
BRCA1 binding is disrupted in the FANCJ breast cancer-associated mutation c.2992-2995delAAGA.
“In addition, BRCA1 binding is disrupted in the FANCJ breast cancer-associated mutation c.2992–2995delAAGA [43].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [43]
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Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1
Cantor, S. B., & Guillemette, S. (2011) · Future Oncology · doi:10.2217/fon.10.191 · Cited by 106 · see citing works
“Along these lines, several FANCJ mutations targeting noncoding genomic DNA have been identified in both breast cancer and FA patients [28,43].”
InfluentialWu, Y., Sommers, J. A., Suhasini, A. N., Leonard, T., Deakyne, J. S., Mazin, A. V., Shin-ya, K., Kitao, H., & Brosh, R. M. (2010) · Blood · doi:10.1182/blood-2009-11-256016 · Cited by 72 · see citing works
Assessing the link between BACH1/FANCJ and MLH1 in DNA crosslink repair
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- Authors
- De Nicolo, A., Tancredi, M., Lombardi, G., Flemma, C. C., Barbuti, S., Di Cristofano, C., Sobhian, B., Bevilacqua, G., Drapkin, R., & Caligo, M. A.
- Affiliations
- 1Cancer Biology, and Departments of
- University of Pisa (IT)
- 4Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, Transplants and New Technologies in Medicine, Section of Oncogenetics, University of Pisa and University Hospital of Pisa, Pisa, Italy
- Brigham and Women's Hospital (US)
- Venue
- Clinical Cancer Research
- Published
- 2008-07-15
- Volume
- 14
- Issue
- 14
- Pages
- 4672-4680
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2561321
- OpenAlex
- W2149943025
- Cited by
- 91
- References
- 53
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 24 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 2 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 2 · 2013: 4 · 2012: 9
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Ovarian Cancer Research Fund (K08 CA108748)
- Associazione Italiana per la Ricerca sul Cancro
- National Cancer Institute (P50CA105009, K08CA108748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- BRIP1, FANCJ, BACH1, germline mutations, breast cancer predisposition, protein stability, DNA helicase, frameshift mutation, premature stop codon, ovarian cancer, early-onset breast cancer, loss of heterozygosity
- MeSH terms
- Adult, Aged, Base Sequence, Breast Neoplasms, DNA Mutational Analysis, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Ovarian Neoplasms, Pedigree, Transfection, Blotting, Western, Germ-Line Mutation, Loss of Heterozygosity, Genetic Predisposition to Disease, Reverse Transcriptase Polymerase Chain Reaction, RNA Helicases, Immunoprecipitation, Fanconi Anemia Complementation Group Proteins
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