title: Overexpressed thioredoxin compensates Fanconi anemia related chromosomal instability.
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.
authors.affiliation: Institut für Biochemie, Freie Universität Berlin, Thielallee 63, D14195 Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kontou
authors.forename: Caroline
authors.initials: C
authors.lastname: Adelfalk
authors.forename: Maria Helena
authors.initials: MH
authors.lastname: Ramirez
authors.forename: Werner
authors.initials: W
authors.lastname: Ruppitsch
authors.forename: Monica
authors.initials: M
authors.lastname: Hirsch-Kauffmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Schweiger
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D015162:Micronucleus Tests; D019913:Nuclear Localization Signals; D012313:RNA / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D019913:Nuclear Localization Signals; D011993:Recombinant Fusion Proteins; D013879:Thioredoxins; D012313:RNA