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 in...

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Vydáno v:Cell reports (Cambridge) Ročník 15; číslo 11; s. 2488 - 2499
Hlavní autoři: Kais, Zeina, Rondinelli, Beatrice, Holmes, Amie, O’Leary, Colin, Kozono, David, D’Andrea, Alan D., Ceccaldi, Raphael
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 14.06.2016
Elsevier
Témata:
Animals
BRCA1 Protein - deficiency
BRCA1 Protein - metabolism
BRCA2 Protein - deficiency
BRCA2 Protein - metabolism
Carrier Proteins - metabolism
Cell Line, Tumor
Cell Survival
DNA End-Joining Repair - genetics
DNA Polymerase theta
DNA Replication - genetics
DNA-Directed DNA Polymerase - metabolism
Endodeoxyribonucleases
Fanconi Anemia Complementation Group D2 Protein - metabolism
Genomic Instability
Humans
Mice, Nude
Mutation - genetics
Neoplasms - genetics
Neoplasms - pathology
Nuclear Proteins - metabolism
Poly(ADP-ribose) Polymerases - metabolism
Ubiquitination
Up-Regulation - genetics
ISSN:2211-1247, 2211-1247
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Shrnutí: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. [Display omitted] •Loss of FANCD2 and BRCA1/2 is synthetic lethal•FANCD2 maintains fork stability in BRCA1/2-deficient cells•FANCD2 promotes alternative end joining (alt-EJ)•FANCD2 overexpression confers resistance to PARP inhibitors Kais et al. show that BRCA1/2-deficient tumors have a compensatory increase in FANCD2 activity. FANCD2 stabilizes stalled replication forks and promotes alternative end joining (alt-EJ) in BRCA1/2-deficient tumors. Loss of FANCD2 in these tumors results in severe DNA repair defects and enhanced cell death.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2016.05.031