Oxidative stress-specific interaction between FANCD2 and FOXO3a.
The molecular pathway by which Fanconi anemia (FA) proteins function in oxidative stress response has not been defined. Here we report the functional interaction of the FA protein Fanconi anemia complementation group D2 (FANCD2) and the forkhead transcription factor forkhead box O 3a (FOXO3a). FOXO3a colocalized with FANCD2 foci in response to oxidative stress. The FANCD2-FOXO3a complex was not detected in cells deficient for the FA core complex component FANCA but could be restored in corrected cells. Consistent with this, a nonmonoubiquitinated FANCD2 mutant failed to bind FOXO3a. Although both mitomycin C and ionizing radiation induced FANCD2 monoubiquitination, neither could induce the association of FANCD2 and FOXO3a. Overexpression of FOXO3a reduced abnormal accumulation of reactive oxygen species, enhanced cellular resistance to oxidative stress, and increased antioxidant gene expression in corrected but not mutant FA-D2 cells. The novel oxidative stress response pathway identified in this study, in which FANCD2 and FOXO3a converge, probably contributes to cellular antioxidant defense.
Li
Jie
J
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Du
Wei
W
Maynard
Suzette
S
Andreassen
Paul R
PR
Pang
Qishen
Q
D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects
D000975:Antioxidants; C499905:FANCD2 protein, human; C499517:FOXO3 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019384:Nucleic Acid Synthesis Inhibitors; D017382:Reactive Oxygen Species; D016685:Mitomycin