FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair
Year: 2016
Type: article
Abstract: BRCA1/2 proteins function in homologous recombination (HR)-mediated DNA repair and cooperate with Fanconi anemia (FA) proteins to maintain genomic integrity through replication fork stabilization. Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2-deficient tumors upregulate Polθ-mediated alternative end-joining (alt-EJ) repair as a survival mechanism. Whether other mechanisms maintain genomic integrity upon loss of BRCA1/2 proteins is currently unknown. Here we show that BRCA1/2-deficient tumors also upregulate FANCD2 activity. FANCD2 is required for fork protection and fork restart in BRCA1/2-deficient tumors. Moreover, FANCD2 promotes Polθ recruitment at sites of damage and alt-EJ repair. Finally, loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These results reveal a synthetic lethal relationship between FANCD2 and BRCA1/2, and they identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork.
Source: Cell Reports
Authors: Zeina Kais, Beatrice Rondinelli, Amie Holmes, Colin O’Leary, David Kozono, Alan D. D’Andrea, Raphael Ceccaldi
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: Characterization of lung cancer radiosensitizers from genome-wide RNAi screens, Mechanism of Bone Marrow Failure in Fanconi Anemia, Regulation of the Fanconi Anemia Pathway by Ubiquitination, Tumor Cell Biology Training Program, Molecular Pathogenesis of Fanconi Anemia, Molecular Pathogenesis of Fanconi Anemia
OpenAlex ID: W2408982653