Cited by 936DNA Repair MechanismsBRCA gene mutations in cancerPARP inhibition in cancer therapy

A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2

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Schlacher, Katharina, Wu, Hong, Jasin, Maria·2012·Cancer Cell

Abstract

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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Crossref · 10.1016/j.ccr.2012.05.015

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  • BRCA1 is implicated in a repair-independent mechanism that protects stalled replication forks from degradation.

    “BRCA1 is implicated in a repair-independent mechanism in protecting stalled replication forks from degradation to maintain genome stability (Schlacher et al., 2012).”
  • BRCA1-deficient cells show significant shortening of fork length after hydroxyurea treatment, indicating degradation of stalled replication forks.

    “As previously shown, BRCA1-deficient cells show significant shortening of fork length following hydroxyurea (HU) treatment indicating degradation of stalled replication forks.”
  • Abraxas is not required for efficient replication restart after hydroxyurea treatment.

    “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).”

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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)
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
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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