Defective mitochondrial peroxiredoxin-3 results in sensitivity to oxidative stress in Fanconi anemia.
Cells from patients with Fanconi anemia (FA), an inherited disorder that includes bone marrow failure and cancer predisposition, have increased sensitivity to oxidative stress through an unknown mechanism. We demonstrate that the FA group G (FANCG) protein is found in mitochondria. Wild-type but not G546R mutant FANCG physically interacts with the mitochondrial peroxidase peroxiredoxin-3 (PRDX3). PRDX3 is deregulated in FA cells, including cleavage by a calpainlike cysteine protease and mislocalization. FA-G cells demonstrate distorted mitochondrial structures, and mitochondrial extracts have a sevenfold decrease in thioredoxin-dependent peroxidase activity. Transient overexpression of PRDX3 suppresses the sensitivity of FA-G cells to H2O2, and decreased PRDX3 expression increases sensitivity to mitomycin C. Cells from the FA-A and -C subtypes also have PRDX3 cleavage and decreased peroxidase activity. This study demonstrates a role for the FA proteins in mitochondria witsh sensitivity to oxidative stress resulting from diminished peroxidase activity. These defects may lead to apoptosis and the accumulation of oxidative DNA damage in bone marrow precursors.
Mukhopadhyay
Sudit S
SS
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Leung
Kathryn S
KS
Hicks
M John
MJ
Hastings
Philip J
PJ
Youssoufian
Hagop
H
Plon
Sharon E
SE
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D019556:COS Cells; D002154:Calpain / Q000378:metabolism; D002522:Chlorocebus aethiops; D005199:Fanconi Anemia / Q000378:metabolism*; D052241:Fanconi Anemia Complementation Group G Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D016685:Mitomycin / Q000494:pharmacology; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D010544:Peroxidases / Q000378:metabolism*; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C499909:FANCG protein, human; D052241:Fanconi Anemia Complementation Group G Protein; D025801:Ubiquitin; D016685:Mitomycin; D006861:Hydrogen Peroxide; D010544:Peroxidases; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D009195:Peroxidase; D002154:Calpain