Fanconi's anaemia cells have normal steady-state levels and repair of oxidative DNA base modifications sensitive to Fpg protein

Will, Olaf; Schindler, Detlev; Boiteux, Serge; Epe, Bernd

doi:10.1016/s0921-8777(98)00043-3

Cited by 17 publications

(8 citation statements)

References 41 publications

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“…It is, however, an indication that GSH has an important role in the protection of cells from DNA damage by endogenously generated ROS, and that it is one of the factors that determines the steadystate level of oxidative DNA damage in cells. The high steadystate level of Fpg-sensitive modifications in the Fanconi's anaemia cells H94-38T4 (Figure 1) was probably not caused by a repair deficiency of the cells, since the removal of additionally induced Fpg-sensitive modifications has been shown to be normal (48).…”

Section: Discussionmentioning

confidence: 94%

Influence of glutathione levels and heat-shock on the steady-state levels of oxidative DNA base modifications in mammalian cells

Will

Mahler²,

Arrigo

et al. 1999

Carcinogenesis

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The effects of thiols, ascorbic acid and thermal stress on the basal (steady-state) levels of oxidative DNA base modifications were studied. In various types of untreated cultured mammalian cells, the levels of total glutathione were found to be inversely correlated with the levels of DNA base modifications sensitive to the repair endonuclease Fpg protein, which include 8-hydroxyguanine (8-oxoG). A depletion of glutathione by treatment with buthionine sulphoximine increased the steady-state level in AS52 Chinese hamster cells by~50%. However, additional thiols in the culture medium did not reduce the level of Fpgsensitive base modifications: 0-10 mM N-acetylcysteine had no effect, whereas cysteine ethylester even increased the oxidative DNA damage at concentrations >0.1 mM. Similarly, ascorbic acid (0-20 mM) failed to reduce the steadystate levels. When AS52 cells were grown at elevated temperature (41°C), the steady-state level of the oxidative DNA modifications increased by 40%, in spite of a concomitant 1.6-fold increase of the cellular level of total glutathione. Depletion of glutathione at 41°C nearly doubled the already elevated level of oxidative damage. A constitutive expression of the heat-shock protein Hsp27 in L929 mouse fibrosarcoma cells at 37°C increased the glutathione level by 60%, but had little effect on the level of oxidative DNA damage.

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Section: Discussionmentioning

confidence: 94%

Influence of glutathione levels and heat-shock on the steady-state levels of oxidative DNA base modifications in mammalian cells

Will

Mahler²,

Arrigo

et al. 1999

Carcinogenesis

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“…Well-established mechanistic information has shown that MMC-associated toxicity is dependent on oxygen levels (Clarke et al 1997;Korkina et al 2000) and is removed by low-molecularweight antioxidants (Raj and Heddle 1980) and by thioredoxin (Trx) overexpression (Ruppitsch et al 1998). Recent reports demonstrate that a) MMC exposure results in an increase in oxidative DNA damage (Pagano et al 2001); b) FA cells fail to accumulate higher MMC adduct levels in DNA than control cells (Rutherford et al 1999;Will et al 1998); and c) the ratio of MMC biadducts to monoadducts (reflective of a DNA repair defect) shows no difference in FA cells compared with normal cells (Rutherford et al 1999). In a previous study, Clarke et al (1997) had shown that MMC-induced apoptosis in FA complementation group C (FA-C) cells occurred under normoxic conditions (associated with redox-cycling mechanisms), whereas MMC was ineffective in causing apoptosis under hypoxic conditions (with prevailing cross-link formation).…”

Section: Xenobiotics Involved In Defining Fa Phenotypementioning

confidence: 99%

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

Pagano¹,

Manini²,

Bagchi³

2003

Environ Health Perspect

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“…(11) However, despite the induction of oxidative DNA damage with MMC, (25) the ratio of biadducts to monoadducts (reflective of a DNA repair defect) is comparable in FA cells and controls. (26) Along with the observation that MMC-induced apoptosis in FA group C (FA-C) cells require normoxic (associated with redox-cycling mechanisms), not hypoxic conditions, (6) the mechanisms of toxicity of MMC in FA-C cells appear to be due primarily to the abnormal redox activities.…”

Section: Introductionmentioning

confidence: 99%

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

Pagano¹,

Youssoufian

2003

BioEssays

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Fanconi anaemia (FA) is a cancer-prone genetic disorder that is characterised by cytogenetic instability and redox abnormalities. Although rare subtypes of FA (B, D1 and D2) have been implicated in DNA repair through links with BRCA1 and BRCA2, such a role has yet to be demonstrated for gene products of the common subtypes. Instead, these products have been strongly implicated in xenobiotic metabolism and redox homeostasis through interactions of FANCC with cytochrome P-450 reductase and with glutathione S-transferase, and of FANCG with cytochrome P-450 2E1, as well as redox-dependent signalling through an interaction between FANCA and Akt kinase. We hypothesise that FA proteins act directly (via FANCC and FANCG) and indirectly (via FANCA, BRCA2 and FANCD2) with the machinery of cellular defence to modulate oxidative stress. The latter interactions may co-ordinate the link between the response to DNA damage and oxidative stress parameters (3, 6-12).

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Fanconi's anaemia cells have normal steady-state levels and repair of oxidative DNA base modifications sensitive to Fpg protein

Cited by 17 publications

References 41 publications

Influence of glutathione levels and heat-shock on the steady-state levels of oxidative DNA base modifications in mammalian cells

Influence of glutathione levels and heat-shock on the steady-state levels of oxidative DNA base modifications in mammalian cells

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

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

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