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 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 H2O2 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.
Park
Su-Jung
SJ
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis 46202, USA.
Ciccone
Samantha L M
SL
Beck
Brian D
BD
Hwang
Byounghoon
B
Freie
Brian
B
Clapp
D Wade
DW
Lee
Suk-Hee
SH
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D003001:Cloning, Molecular; D004249:DNA Damage; D004260:DNA Repair; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D019281:Dimerization; D004220:Disulfides; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005033:Ethylmaleimide / Q000494:pharmacology; D005199:Fanconi Anemia / Q000378:metabolism*; D052217:Fanconi Anemia Complementation Group A Protein; D052241:Fanconi Anemia Complementation Group G Protein; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D008954:Models, Biological; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000502:physiology*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004220:Disulfides; C498471:FANCA protein, human; C499909:FANCG protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D052241:Fanconi Anemia Complementation Group G Protein; D016877:Oxidants; D011506:Proteins; D016685:Mitomycin; D006861:Hydrogen Peroxide; D005982:Glutathione Transferase; D005033:Ethylmaleimide; D010100:Oxygen