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`cafe au lait' spots of FA. The observation of thioredoxin reduction in FA cells permits insight into the molecular phathophysiology of FA.

Fanconi anaemia proteins: Major roles in cell protection against oxidative damage

“…Both phase 1 and phase 2 activities appear to be regulated by these proteins, and both cell culture models and mouse models of FA reinforce the view that abnormal adaptation to oxidative stress lies at the core of the observation that FA cells display alterations in a number of oxidative stress parameters. (3,4,(7)(8)(9)(10)(11)(12) The indirect effects appear to be carried out in collaboration with several proteins that are active in DNA repair, and we propose that FANCD2 and BRCA2 serve as critical links of these two functions. Thus, it is not surprising that these two functions have been difficult to disentangle in the context of the fundamental pathogenesis of FA.…”

p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes

“…For example, of the 2 well-known p38 activators, MEKK1 and ASK1, 47,48 ASK1 is of substantial interest. Because its activity is inhibited by proteins [49][50][51] known to interact with 6,8 or to be stabilized by 52,53 FA proteins, it has been implicated in aberrant TNF␣ responses in Fancc-deficient murine embryonic fibroblasts. 20,54 FANCA and FANCC mutations account for at least 65% of patients with FA worldwide.…”

Oxidative stress-related mechanisms are associated with xenobiotics exerting excess toxicity to Fanconi anemia cells.

“…A consistent body of evidence has been accumulated since then, both related to phenotypic redox abnormalities and related to the involvement of FA proteins in redox pathways (Ahmad et al 2002;Bogliolo et al 2002;Pagano et al 1998;Pagano and Korkina 2000;Pagano and Youssoufian 2003), as summarized in Table 4. FA cells are characterized by a) excess oxidative DNA damage ] in hydrogen peroxide-exposed FA cells (Takeuchi and Morimoto 1993), and in freshly drawn white blood cells from FA patients (Degan et al 1995); b) increased oxygen sensitivity (Joenje et al 1981) and sensitivity to free iron (Poot et al 1996); c) correction of chromosomal abnormalities by either antioxidant enzymes or by low-molecularweight antioxidants (Dallapiccola et al 1985;Nordenson 1977;Raj and Heddle 1980); d) excess plasma levels of clastogenic factor (Emerit et al 1995) and of tumor necrosis factor-α (TNF-α; Dufour et al 2003;Schulz and Shahidi 1993); e) involvement of redoxactive cytokines, such as TNF-α and interferon-γ (Dufour et al 2003;Pearl-Yafe et al 2003), and of inducible nitric oxide synthase (Hadjur and Jirik 2003); and d) an involvement of Trx, which corrects MMC and DEB sensitivity in FA cells (Ruppitsch et al 1998) and occurs in lower-than-normal levels in FA fibroblasts (Kontou et al 2002). Together, a well-established body of evidence on FA cellular phenotype, along with the roles for some FA proteins in redox pathways (Bogliolo et al 2002;Pagano and Youssoufian 2003), combine to support a central role for oxidative stress both in FA cellular phenotype and in FA protein functions.…”