Journal
CELL REPORTS
Volume 15, Issue 11, Pages 2488-2499Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.031
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Funding
- Ovarian Cancer Research Fellowship (OCRF) Ann Shreiber Mentored Investigator Award
- Italian Association for Cancer Research (AIRC) Fellowship
- Claudia Adams Barr Program award
- Stand Up To Cancer (SU2C) - Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant [SU2C-AACR-DT16-15]
- American Association for Cancer Research
- NIH [R01DK43889, R37HL052725]
- Breast Cancer Research Foundation
- Fanconi Anemia Research Fund
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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 BRCA1/2deficient tumors upregulate Polq-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 Polq recruitment at sites of damage and altEJ 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.
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