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Overexpressed thioredoxin compensates Fanconi anemia related chromosomal instability

Oncogene volume 21, pages 2406–2412 (2002)Cite this article

Abstract

The cause of the molecular defect of Fanconi anemia (FA) remains unknown. Cells from patients with FA exert an elevated spontaneous chromosomal instability which is further triggered by mitomycin C. The induced lability is reduced by overexpression of thioredoxin which is not the case for spontaneous instability. However, both are eliminated by overexpression of thioredoxin cDNA with an added nuclear localization signal. This implies that thioredoxin is lacking in the nuclei of FA cells. The total thioredoxin content in all FA cells tested is reduced. The resultant lack of nuclear thioredoxin can be the explanation for the major symptomatology in FA. Since thioredoxin is known to be the reactive cofactor of ribonucleotid reductase its shortcoming reduces the supply of deoxyribonucleotides thus hindering the DNA and replication repair with resultant chromosomal breaks. Furthermore, depression of tyrosine hydroxylase, the key enzyme of melanine synthesis, could be the basis for the pathognomotic ‘café au lait’ spots of FA. The observation of thioredoxin reduction in FA cells permits insight into the molecular phathophysiology of FA.

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Acknowledgements

We acknowledge with thanks Klaus Hennig for the overexpression and isolation of thioredoxin and Dr Rossi for raising antithioredoxin antibodies. We are very grateful to Prof Dr D Hirsch-Kauffmann Jokl, New York for editing suggestions. This work was possible through the generous support by grants from Thyssen-foundation (20002084).

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Authors and Affiliations

  1. Institut für Biochemie, Freie Universität Berlin, Thielallee 63, Berlin, D14195, Germany

    Maria Kontou, Caroline Adelfalk, Maria Helena Ramirez, Werner Ruppitsch & Manfred Schweiger

  2. Institut für Medizinische Biologie und Humangenetik, Universität Innsbruck, Schöpfstr.41, Innsbruck, A6020, Austria

    Monica Hirsch-Kauffmann

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  1. Maria Kontou
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Correspondence to Manfred Schweiger.

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Kontou, M., Adelfalk, C., Ramirez, M. et al. Overexpressed thioredoxin compensates Fanconi anemia related chromosomal instability. Oncogene 21, 2406–2412 (2002). https://doi.org/10.1038/sj.onc.1205299

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