FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair.
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.
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Zeina
Z
Kais
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Beatrice
B
Rondinelli
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Amie
A
Holmes
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Colin
C
O'Leary
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
David
D
Kozono
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu.
Alan D
AD
D'Andrea
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: raphael_ceccaldi@dfci.harvard.edu.
Raphael
R
Ceccaldi
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000378:metabolism; D024682:BRCA2 Protein / Q000172:deficiency* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D059766:DNA End-Joining Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004706:Endodeoxyribonucleases; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation / Q000235:genetics; D000097462:DNA Polymerase theta
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D002352:Carrier Proteins; D004259:DNA-Directed DNA Polymerase; D004706:Endodeoxyribonucleases; D052236:Fanconi Anemia Complementation Group D2 Protein; D009687:Nuclear Proteins; D011065:Poly(ADP-ribose) Polymerases; D000097462:DNA Polymerase theta; C410741:RBBP8 protein, human