Cancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism
Autoři:
Diana C. Odermatt aff001; Wei Ting C. Lee aff002; Sebastian Wild aff001; Stanislaw K. Jozwiakowski aff001; Eli Rothenberg aff002; Kerstin Gari aff001
Působiště autorů:
Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
aff001; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, United States of America
aff002
Vyšlo v časopise:
Cancer-associated mutations in the iron-sulfur domain of FANCJ affect G-quadruplex metabolism. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008740
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008740
Souhrn
FANCJ/BRIP1 is an iron-sulfur (FeS) cluster-binding DNA helicase involved in DNA inter-strand cross-link (ICL) repair and G-quadruplex (G4) metabolism. Mutations in FANCJ are associated with Fanconi anemia and an increased risk for developing breast and ovarian cancer. Several cancer-associated mutations are located in the FeS domain of FANCJ, but how they affect FeS cluster binding and/or FANCJ activity has remained mostly unclear. Here we show that the FeS cluster is indispensable for FANCJ’s ability to unwind DNA substrates in vitro and to provide cellular resistance to agents that induce ICLs. Moreover, we find that FANCJ requires an intact FeS cluster for its ability to unfold G4 structures on the DNA template in a primer extension assay with the lagging-strand DNA polymerase delta. Surprisingly, however, FANCJ variants that are unable to bind an FeS cluster and to unwind DNA in vitro can partially suppress the formation of replisome-associated G4 structures that we observe in a FANCJ knock-out cell line. This may suggest a partially retained cellular activity of FANCJ variants with alterations in the FeS domain. On the other hand, FANCJ knock-out cells expressing FeS cluster-deficient variants display a similar–enhanced–sensitivity towards pyridostatin (PDS) and CX-5461, two agents that stabilise G4 structures, as FANCJ knock-out cells. Mutations in FANCJ that abolish FeS cluster binding may hence be predictive of an increased cellular sensitivity towards G4-stabilising agents.
Klíčová slova:
ATP hydrolysis – Cysteine – DNA replication – DNA structure – DNA-binding proteins – Enzyme structure – Genetic causes of cancer – Helicases
Zdroje
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