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

Pagano, Giovanni; Youssoufian, Hagop

doi:10.1002/bies.10283

Cited by 64 publications

(40 citation statements)

References 82 publications

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“…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).…”

Section: Prooxidant State In Fa Phenotypementioning

confidence: 87%

“…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.…”

Section: Prooxidant State In Fa Phenotypementioning

confidence: 99%

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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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Section: Prooxidant State In Fa Phenotypementioning

confidence: 87%

Section: Prooxidant State In 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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“…However, precise molecular roles of FA proteins, presumed to mediate protection from DNA and oxidative damage (Pagano and Youssoufian, 2003;Kennedy and D'Andrea, 2005), have remained relatively elusive. In response to DNA damage or during S phase, a cooperative network of FA protein interactions results in the assembly of a multiprotein nuclear core complex followed by the monoubiquitination and translocation of FANCD2 and FANCI to chromatinassociated nuclear foci.…”

Section: Discussionmentioning

confidence: 99%

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

et al. 2008

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Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.

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“…Conditions-Increasing evidence points to a role for FANC proteins in redox signaling and the repair of oxidative damages (22)(23)(24).…”

Section: Multimerization Of Fanc Proteins Under Oxidizingmentioning

confidence: 99%

“…Treatment of Cells with Mitomycin C Also Induces a Multimeric Complex of FANCA and FANCG in Vivo-FANC cells are highly sensitive to MMC, a DNA-damaging agent that primarily induces interstrand cross-link DNA damage but also can cause oxidative damage as well as other types of DNA damages (intrastrand cross-link and monoadduct) (24,26). We therefore examined whether MMC treatment also induces a multimeric complex of FANC proteins in vivo.…”

Section: Multimerization Of Fanc Proteins Under Oxidizingmentioning

confidence: 99%

Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins

Park

Ciccone

Beck

et al. 2004

Journal of Biological Chemistry

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Fanconi anemia (FANC) is a heterogeneous genetic disorder characterized by a hypersensitivity to DNAdamaging agents, chromosomal instability, and defective DNA repair. Eight FANC genes have been identified so far, and five of them (FANCA, -C, -E, -F, and -G) assemble in a multinuclear complex and function at least in part in a complex to activate FANCD2 by monoubiquitination. Here Fanconi anemia (FANC) 1 is an autosomal recessive disorder characterized by chromosomal instability and defective DNA repair, and FANC-deficient cells exhibit extreme sensitivity toward oxygen and DNA-cross-linking agents such as diepoxybutane and mitomycin C (1-3). The gene products of eight complementation groups of FANC have been identified and cloned (FANCA, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL) (1-3). Mutations in any of the eight different genes lead to FANC disease, a degree of genetic heterogeneity comparable with that of other DNA repair disorders, suggesting that each group represents a distinct protein.FANCA and FANCG proteins are part of a large nuclear protein complex required for their function, and the disruption of this complex results in the specific cellular and clinical phenotype common to most FANC complementation groups (4). FANCA gene encodes a 162-kDa phosphoprotein and its phosphorylation correlated with FANCA/FANCC protein accumulation in the nucleus (5). FANCA mutant cells isolated from a FANC patient were defective in their phosphorylation and failed to bind to FANCC. Furthermore, a mutant FANCA protein failed to complement the mitomycin C (MMC) sensitivity of FANCAϪ/Ϫ cells, suggesting that FANCA phosphorylation may be involved in FANCC interaction, nuclear localization of FANCA, or its function in cross-link repair. FANCG gene encodes a 65-kDa protein that has been identified as human XRCC9. XRCC9 (FANCG) complements the Chinese hamster ovary mutant UV-40 cell line that is hypersensitive to UV, ionizing radiation, simple alkylating agents, and DNA-crosslinking agents (6, 7). The mutant cells also show a high level of spontaneous chromosomal aberrations that can be fully corrected by introduction of XRCC9 cDNA transformants (7). The possibility of the involvement of FANC proteins in DNA repair was strengthened by recent findings on the interaction of FANCD1 with BRCA1 following DNA damage (8). FANCD1 is identical to BRCA2 gene and is unique among FANC genes in that it is essential for the formation of Rad51 foci in response to ionizing radiation (9), suggesting that it may be involved in homologous recombination-mediated strand break repair.Cells lacking FANC gene showed a hypersensitive phenotype following H 2 O 2 treatment, suggesting a role for FANC proteins in redox signaling and repair of oxidative DNA damages (Refs. 10 -13 and data not shown). Interaction between FANCA and FANCG was well established by coimmunoprecipitation, cellular localization, and yeast two-hybrid analysis (4, 14 -18). Although the detailed functions of FANC proteins have yet to be determined, there is a growi...

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

Cited by 64 publications

References 82 publications

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

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

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins

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