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

Abstract

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...

Inflammatory ROS promote and cooperate with the Fanconi anemia mutation for hematopoietic senescence

“…The FA proteins are thus believed to play important roles in the maintenance of hematopoiesis. Consistent with the observations that cells derived from FA patients are intolerant of oxidative stress, it has been reported that FA proteins, particularly the complementation group C (FANCC) protein, play a crucial role in oxidative-stress signaling in a variety of cell types including hematopoietic cells (Kruyt et al, 1998;Cumming et al, 2001;Hadjur et al, 2001;Futaki et al, 2002;Park et al, 2004;Saadatzadeh et al, 2004;Pagano et al, 2005). More recently, cytokine hypersensitivity of FA hematopoietic cells to apoptotic cues has also been proposed as a major factor in the pathogenesis of BM failure in three FA mouse models…”

Constitutive Activation of Caspase-3 and Poly ADP Ribose Polymerase Cleavage in Fanconi Anemia Cells

“…FA cells are sensitive to ROS, thus acquiring abnormalities in several redox status end points (13)(14)(15). FANCA and FANCG are redox-sensitive proteins that are multimerized to form a nuclear complex in response to oxidative stress (16). Not surprisingly, the survival of human primary FA BM cells can be ameliorated by reducing oxidative stress (14).…”

Stress and DNA repair biology of the Fanconi anemia pathway

“…For example, FANCA and FANCG are sensitive to redox conditioning, such that hydrogen peroxide treatment triggers complex formation of these FA proteins. 120 The antioxidant tempol displayed tumor onset and protective effects against oxidative damage in Fancd2 2/2 mice.…”