Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins

Fanconi anemia (FANC) is a heterogeneous genetic disorder characterized by a hypersensitivity to DNA-damaging agents, chromosomal instability, and defective DNA repair. Eight FANC genes have been identified so far, and five of them ( FANCA , -C , -E , -F , and -G ) assemble in a multinuclear complex...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-07, Vol.279 (29), p.30053-30059
Main Authors: Park, Su-Jung, Ciccone, Samantha L M, Beck, Brian D, Hwang, Byounghoon, Freie, Brian, Clapp, D Wade, Lee, Suk-Hee
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Cloning, Molecular
COS Cells
Dimerization
Disulfides
DNA Damage
DNA Repair
DNA, Complementary - metabolism
DNA-Binding Proteins - physiology
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Ethylmaleimide - pharmacology
Fanconi Anemia - metabolism
Fanconi Anemia Complementation Group A Protein
Fanconi Anemia Complementation Group G Protein
Glutathione Transferase - metabolism
HeLa Cells
Humans
Hydrogen Peroxide - chemistry
Hydrogen Peroxide - pharmacology
Mitomycin - pharmacology
Models, Biological
Oxidants - pharmacology
Oxidation-Reduction
Oxidative Stress
Oxygen - metabolism
Precipitin Tests
Protein Structure, Tertiary
Proteins - physiology
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Summary:Fanconi anemia (FANC) is a heterogeneous genetic disorder characterized by a hypersensitivity to DNA-damaging agents, chromosomal instability, and defective DNA repair. Eight FANC genes have been identified so far, and five of them ( FANCA , -C , -E , -F , and -G ) assemble in a multinuclear complex and function at least in part in a complex to activate FANCD2 by monoubiquitination. Here we show that FANCA and FANCG are redox-sensitive proteins that are multimerized and/or form a nuclear complex in response to oxidative stress/damage. Both FANCA and FANCG proteins exist as monomers under non-oxidizing conditions, whereas they become multimers following H 2 O 2 treatment. Treatment of cells with oxidizing agent not only triggers the multimeric complex of FANCA and FANCG in vivo but also induces the interaction between FANCA and FANCG. N -Ethylmaleimide treatment abolishes multimerization and interaction of FANCA and FANCG in vitro . Taken together, our results lead us to conclude that FANCA and FANCG uniquely respond to oxidative damage by forming complex(es) via intermolecular disulfide linkage(s), which may be crucial in forming such complexes and in determining their function.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M403527200