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A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2
Open accessAbstract
Genes mutated in patients with Fanconi anemia (FA) interact with the DNA repair genes BRCA1 and BRCA2/FANCD1 to suppress tumorigenesis, but the molecular functions ascribed to them cannot fully explain all of their cellular roles. Here, we show a repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation. Fork protection is surprisingly rescued in FANCD2-deficient cells by elevated RAD51 levels or stabilized RAD51 filaments. Moreover, FANCD2-mediated fork protection is epistatic with RAD51 functions, revealing an unanticipated fork protection pathway that connects FA genes to RAD51 and the BRCA1/2 breast cancer suppressors. Collective results imply a unified molecular mechanism for repair-independent functions of FA, RAD51, and BRCA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.
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“BRCA1 is implicated in a repair-independent mechanism in protecting stalled replication forks from degradation to maintain genome stability (Schlacher et al., 2012).”
From The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression (2014) · cites this paper as Schlacher et al., 2012
In the citing paper
“As previously shown, BRCA1-deficient cells show significant shortening of fork length following hydroxyurea (HU) treatment indicating degradation of stalled replication forks.”
From The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression (2014) · cites this paper as Schlacher et al., 2012
In the citing paper
“In addition, Abraxas did not appear to be required for efficient replication restart after HU treatment (data not shown), consistent with published observation that BRCA1 is not required for replication recovery (Schlacher et al., 2012).”
From The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression (2014) · cites this paper as Schlacher et al., 2012
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Flagged first, then by citations
1 of the 46 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Schroeder, 1964, [Spontaneous chromosome aberrations in familial panmyelopathy], Humangenetik, 1, 194
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Metadata
- Authors
- Schlacher, K., Wu, H., & Jasin, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- Corresponding author
- Schlacher, Katharina
- Jasin, Maria
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 22
- Issue
- 1
- Pages
- 106-116
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3954744
- OpenAlex
- W2096380982
- Cited by
- 936
- References
- 46
- Citations by year
- 2026: 40 · 2025: 56 · 2024: 80 · 2023: 70 · 2022: 69 · 2021: 91 · 2020: 86 · 2019: 63 · 2018: 83 · 2017: 74 · 2016: 87 · 2015: 53 · 2014: 50 · 2013: 27 · 2012: 7
- FWCI
- 17.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA121110, P01-CA94060, P01CA094060)
- National Institute of General Medical Sciences (R01 GM54668, R01GM054668)
- 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
- Fanconi anemia, replication fork protection, FANCD2, RAD51, BRCA1, BRCA2, DNA repair, epistasis, genomic instability, tumor suppression
- MeSH terms
- Cell Line, Transformed, DNA Replication, Fanconi Anemia, Humans, Genes, BRCA1, Genes, BRCA2, BRCA2 Protein, Genomic Instability, Rad51 Recombinase
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