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.

[1]  Weidong Wang,et al.  Evidence for subcomplexes in the Fanconi anemia pathway. , 2006, Blood.

[2]  L. Thompson.  Unraveling the Fanconi anemia–DNA repair connection , 2005, Nature Genetics.

[3]  Xiaoling Zhang,et al.  Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. , 2005, Blood.

[4]  N. Colburn,et al.  p53 translocation to mitochondria precedes its nuclear translocation and targets mitochondrial oxidative defense protein-manganese superoxide dismutase. , 2005, Cancer research.

[5]  R. Kolodner,et al.  A biological network in Saccharomyces cerevisiae prevents the deleterious effects of endogenous oxidative DNA damage. , 2005, Molecular cell.

[6]  J. Mi,et al.  The Fanconi anemia core complex associates with chromatin during S phase. , 2005, Blood.

[7]  G. Pals,et al.  X-linked inheritance of Fanconi anemia complementation group B , 2004, Nature Genetics.

[8]  Sue Goo Rhee,et al.  Peroxiredoxin III, a Mitochondrion-specific Peroxidase, Regulates Apoptotic Signaling by Mitochondria* , 2004, Journal of Biological Chemistry.

[9]  D. Clapp,et al.  Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins* , 2004, Journal of Biological Chemistry.

[10]  Anthony A High,et al.  The Fanconi Anemia Core Complex Forms Four Complexes of Different Sizes in Different Subcellular Compartments* , 2004, Journal of Biological Chemistry.

[11]  H. Joenje,et al.  Multiple TPR motifs characterize the Fanconi anemia FANCG protein. , 2004, DNA repair.

[12]  C. Bishop,et al.  A novel ubiquitin ligase is deficient in Fanconi anemia , 2003, Nature Genetics.

[13]  N. C. Price,et al.  Structure-Function Analysis of Recombinant Substrate Protein 22 kDa (SP-22) , 2003, Journal of Biological Chemistry.

[14]  K. Daniel,et al.  Association of mitochondrial calpain activation with increased expression and autolysis of calpain small subunit in an early stage of apoptosis. , 2003, International journal of molecular medicine.

[15]  S. Orkin,et al.  Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression , 2003, Nature.

[16]  Alan D. D'Andrea.  Fanconi anemia , 2003, Current Biology.

[17]  G. Powis,et al.  Increased expression of mitochondrial peroxiredoxin-3 (thioredoxin peroxidase-2) protects cancer cells against hypoxia and drug-induced hydrogen peroxide-dependent apoptosis. , 2003, Molecular cancer research : MCR.

[18]  S. Kang,et al.  Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice. , 2003, Blood.

[19]  H. Youssoufian,et al.  Fanconi anaemia proteins: major roles in cell protection against oxidative damage. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[20]  Kap-Seok Yang,et al.  Reversing the Inactivation of Peroxiredoxins Caused by Cysteine Sulfinic Acid Formation , 2003, Science.

[21]  G. Bagby,et al.  The Anti-apoptotic Function of Hsp70 in the Interferon-inducible Double-stranded RNA-dependent Protein Kinase-mediated Death Signaling Pathway Requires the Fanconi Anemia Protein, FANCC* , 2002, The Journal of Biological Chemistry.

[22]  Joon-Hyuk Choi,et al.  Overexpression of mitochondrial thioredoxin reductase and peroxiredoxin III in hepatocellular carcinomas. , 2002, Anticancer research.

[23]  S. Krajewski,et al.  Calpain and Mitochondria in Ischemia/Reperfusion Injury* , 2002, The Journal of Biological Chemistry.

[24]  Chi V. Dang,et al.  The c-Myc target gene PRDX3 is required for mitochondrial homeostasis and neoplastic transformation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  F. Hanaoka,et al.  Molecular biology of Fanconi anaemia—an old problem, a new insight , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[26]  A. D’Andrea,et al.  Fanconi anemia and DNA repair. , 2001, Human molecular genetics.

[27]  R. Gronostajski,et al.  Differential Interactions of Specific Nuclear Factor I Isoforms with the Glucocorticoid Receptor and STAT5 in the Cooperative Regulation of WAP Gene Transcription , 2001, Molecular and Cellular Biology.

[28]  M. Buchwald,et al.  Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase. , 2001, Blood.

[29]  A. D’Andrea,et al.  Functional analysis of patient-derived mutations in the Fanconi anemia gene, FANCG/XRCC9. , 2001, Experimental hematology.

[30]  M. Buchwald,et al.  Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1 , 2001, Nature Medicine.

[31]  D. Noh,et al.  Overexpression of peroxiredoxin in human breast cancer. , 2001, Anticancer research.

[32]  S. Kajigaya,et al.  Fanconi anemia protein, FANCG, is a phosphoprotein and is upregulated with FANCA after TNF-alpha treatment. , 2001, Biochemical and biophysical research communications.

[33]  N D Marchenko,et al.  Death Signal-induced Localization of p53 Protein to Mitochondria , 2000, The Journal of Biological Chemistry.

[34]  L. Tsai,et al.  Neurotoxicity induces cleavage of p35 to p25 by calpain , 2000, Nature.

[35]  G. Pagano,et al.  Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions: further insights into the role for oxidative stress in Fanconi's anaemia phenotype. , 2000, Carcinogenesis.

[36]  Q. Waisfisz,et al.  A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Y. Murasato,et al.  Antioxidant Function of the Mitochondrial Protein SP-22 in the Cardiovascular System* , 1999, The Journal of Biological Chemistry.

[38]  S. Kajigaya,et al.  Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression. , 1998, Blood.

[39]  S. Rhee,et al.  Mammalian Peroxiredoxin Isoforms Can Reduce Hydrogen Peroxide Generated in Response to Growth Factors and Tumor Necrosis Factor-α* , 1998, The Journal of Biological Chemistry.

[40]  W. Ruppitsch,et al.  Overexpression of thioredoxin in Fanconi anemia fibroblasts prevents the cytotoxic and DNA damaging effect of mitomycin C and diepoxybutane , 1998, FEBS letters.

[41]  S. Takahashi,et al.  SP-22 is a thioredoxin-dependent peroxide reductase in mitochondria. , 1997, European journal of biochemistry.

[42]  Anne Robbins,et al.  Identification of proteins that interact with a protein of interest: Applications of the yeast two-hybrid system , 1997, Molecular and Cellular Biochemistry.

[43]  H. Klocker,et al.  The role of oxygen metabolism for the pathological phenotype of Fanconi anemia , 1997, Human Genetics.

[44]  B. Alter.  Hematologic abnormalities in Fanconi anemia. , 1995, Blood.

[45]  B. Alter.  Hematologic abnormalities in Fanconi anemia [letter; comment] , 1995 .

[46]  R. Gale,et al.  Hematologic Abnormalities in Fanconi Anemia: An International Fanconi Anemia Registry Study , 1994 .

[47]  B. Dallapiccola,et al.  Partial correction of chromosome instability in Fanconi anemia by desferrioxamine , 1989, Human Genetics.

[48]  H. Hoehn,et al.  Fanconi anemia mutation causes cellular susceptibility to ambient oxygen. , 1988, American journal of human genetics.

[49]  H. Wortelboer,et al.  Antioxidant status of Fanconi anemia fibroblasts , 1987, Human Genetics.

[50]  F. Denizot,et al.  Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. , 1986, Journal of immunological methods.

[51]  D. Botstein,et al.  Yeast genes fused to beta-galactosidase in Escherichia coli can be expressed normally in yeast. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[52]  H. Joenje,et al.  Oxygen-dependence of chromosomal aberrations in Fanconi's anaemia , 1981, Nature.

[53]  H. Hoehn,et al.  Partial correction of chromosome instability in Fanconi anemia by desferrioxamine , 2004, Human Genetics.

[54]  S. Kajigaya,et al.  The FANCG Fanconi anemia protein interacts with CYP2E1: possible role in protection against oxidative DNA damage. , 2002, Carcinogenesis.

[55]  A. Manning,et al.  Fanconi anemia protein complex is a novel target of the IKK signalsome , 2002, Journal of cellular biochemistry.

[56]  G. Salido,et al.  Release of Calcium from Mitochondrial and Nonmitochondrial Intracellular Stores in Mouse Pancreatic Acinar Cells by Hydrogen Peroxide , 2001, The Journal of Membrane Biology.

[57]  B. Xue,et al.  Rapid colorimetric assay for cell growth and survival in application of immunotoxicology , 1988 .

[58]  G. Fanconi,et al.  Fragility and spiralization anomalies of the chromosomes in three cases, including fraternal twins, with Fanconi's anemia, type Estren-Dameshek. , 1978, Cytogenetics and cell genetics.