Mutations in the gene defective in Fanconi anemia complementation group C, FAC, are responsible for a subset of Fanconi anemia, a group of autosomal recessive disorders characterized by chromosomal instability, hypersensitivity to cross-linking agents, and cancer susceptibility. Although abnormalities in DNA repair have been suspected, localization of the FAC gene product to the cytoplasm has cast doubt on such a mechanism. Monitoring of interstrand DNA cross-linking shows that the predominant defect in group C cells is in the initial induction of cross-links, not in repair synthesis. Both the cross-linking defect and the enhanced cytotoxicity of cross-linkers on Fanconi anemia group C cells are corrected completely by cytoplasmic isoforms of the FAC protein, but not by an isoform targeted to the nucleus. The ability of FAC to correct these phenotypic abnormalities reaches a maximum threshold despite overexpression leading to higher levels of cytosolic protein. These results demonstrate that cytoplasmic localization is essential for the intracellular activity of the FAC protein. It is proposed that this activity is coupled to a cytoplasmic defense mechanism against a specific class of genotoxic agents.
H Youssoufian
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HROB Is Implicated in DNA Replication
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Genes | 2024 |
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Genetic Predisposition to Cancer, 2Ed
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Oxidant Hypersensitivity of Fanconi Anemia Type C-deficient Cells Is Dependent on a Redox-regulated Apoptotic Pathway
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The Journal of biological chemistry | 2004 |
The Fanconi Anemia Core Complex Forms Four Complexes of Different Sizes in Different Subcellular Compartments
A Thomashevski, AA High, M Drozd, J Shabanowitz, DF Hunt, PA Grant, GM Kupfer |
The Journal of biological chemistry | 2004 |
Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines
S Hadjur, FR Jirik |
Blood | 2003 |
Chromosomal Instability and Aging: Basic Science and Clinical Implications
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Chromosomal Instability and Aging: Basic Science and Clinical Implications | 2003 |
Lymphoma development in Bax transgenic mice is inhibited by Bcl-2 and associated with chromosomal instability
JJ Luke, CI van de Wetering, CM Knudson |
Cell Death and Differentiation | 2003 |
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Blood | 2003 |
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Experimental Hematology | 2002 |
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2002 | |
Correction of cross-linker sensitivity of Fanconi anemia group F cells by CD33-mediated protein transfer
RK Holmes, K Harutyunyan, M Shah, H Joenje, H Youssoufian |
Blood | 2001 |
Positional Cloning of a Novel Fanconi Anemia Gene, FANCD2
C Timmers, T Taniguchi, J Hejna, C Reifsteck, L Lucas, D Bruun, M Thayer, B Cox, S Olson, AD D'Andrea, R Moses, M Grompe |
Molecular Cell | 2001 |
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Trends in Molecular Medicine | 2001 |
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Experimental Hematology | 2001 |
Functional Analysis of the Putative Peroxidase Domain of FANCA, the Fanconi Anemia Complementation Group A Protein
J Ren, H Youssoufian |
Molecular Genetics and Metabolism | 2001 |
Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1
RC Cumming, J Lightfoot, K Beard, H Youssoufian, PJ O'Brien, M Buchwald |
Nature Medicine | 2001 |
Functional correction of FA-C cells withFANCC suppresses the expression of interferon γ–inducible genes
SR Fagerlie, J Diaz, TA Christianson, K McCartan, W Keeble, GR Faulkner, GC Bagby |
Blood | 2001 |
Do Fanconi anemia genes control cell response to cross-linking agents by modulating cytochrome P-450 reductase activity?
FA Kruyt, H Youssoufian |
Drug Resistance Updates | 2000 |
DNA replication is required To elicit cellular responses to psoralen-induced DNA interstrand cross-links
YM Akkari, RL Bateman, CA Reifsteck, SB Olson, M Grompe |
Molecular and cellular biology | 2000 |
Investigation of Fanconi Anemia Protein Interactions by Yeast Two-Hybrid Analysis
PA Huber, AL Medhurst, H Youssoufian, CG Mathew |
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Current Clinical Practice: Advances in the Genetics and Biology of Fanconi Anaemia
AJ Tipping, CG Mathew |
Hematology | 2000 |
Posttranscriptional cell cycle–dependent regulation of human FANCC expression
MC Heinrich, KV Silvey, S Stone, AJ Zigler, DJ Griffith, M Montalto, L Chai, Y Zhi, ME Hoatlin |
Blood | 2000 |
Interferon-γ–induced apoptotic responses of Fanconi anemia group C hematopoietic progenitor cells involve caspase 8–dependent activation of caspase 3 family members
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Blood | 2000 |
The Fanconi anemia group C gene product modulates apoptotic responses to tumor necrosis factor-α and Fas ligand but does not suppress expression of receptors of the tumor necrosis factor receptor superfamily
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Experimental Hematology | 1999 |
Localization of the bloom syndrome helicase to punctate nuclear structures and the nuclear matrix and regulation during the cell cycle: Comparison with the werner's syndrome helicase
V Gharibyan, H Youssoufian |
Molecular Carcinogenesis | 1999 |
Interstrand cross-links induce DNA synthesis in damaged and undamaged plasmids in mammalian cell extracts
L Li, CA Peterson, X Lu, P Wei, RJ Legerski |
Molecular and cellular biology | 1999 |
Resistance to Mitomycin C Requires Direct Interaction between the Fanconi Anemia Proteins FANCA and FANCG in the Nucleus through an Arginine-rich Domain
FA Kruyt, F Abou-Zahr, H Mok, H Youssoufian |
The Journal of biological chemistry | 1999 |
Expression of the Fanconi Anemia Group A Gene (Fanca) During Mouse Embryogenesis
R Abu-Issa, G Eichele, H Youssoufian |
Blood | 1999 |
Loss of FancC Function Results in Decreased Hematopoietic Stem Cell Repopulating Ability
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Blood | 1999 |
Protein Replacement by Receptor-Mediated Endocytosis Corrects the Sensitivity of Fanconi Anemia Group C Cells to Mitomycin C
H Youssoufian, FA Kruyt, X Li |
Blood | 1999 |
Is Fanconi anemia caused by a defect in the processing of DNA damage?
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Mutation Research/DNA Repair | 1998 |
Fanconi's anemia: what have we learned from the genes so far?
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Blood | 1998 |
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Blood | 1998 |
The Fanconi Anemia Proteins FAA and FAC Function in Different Cellular Compartments to Protect Against Cross-Linking Agent Cytotoxicity
FA Kruyt, H Youssoufian |
Blood | 1998 |
Molecular Chaperone GRP94 Binds to the Fanconi Anemia Group C Protein and Regulates Its Intracellular Expression
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Blood | 1998 |
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Blood | 1998 |
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Journal of Clinical Investigation | 1997 |
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Genetic Testing | 1997 |
Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells
RK Rathbun, GR Faulkner, MH Ostroski, TA Christianson, G Hughes, G Jones, R Cahn, R Maziarz, G Royle, W Keeble, MC Heinrich, M Grompe, PA Tower, GC Bagby |
Blood | 1997 |
Cytoplasmic Localization of a Functionally Active Fanconi Anemia Group A–Green Fluorescent Protein Chimera in Human 293 Cells
FA Kruyt, Q Waisfisz, LM Dijkmans, MA Hermsen, H Youssoufian, F Arwert, H Joenje |
Blood | 1997 |
Phenotypic Consequences of Mutations in the Fanconi Anemia FAC Gene: An International Fanconi Anemia Registry Study
AP Gillio, PC Verlander, SD Batish, PF Giampietro, AD Auerbach |
Blood | 1997 |