The fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation (original) (raw)
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Function of the Fanconi anemia pathway in Fanconi anemia complementation group F and D1 cells
Experimental Hematology, 2001
Objective. Fanconi anemia (FA) is a human autosomal-recessive cancer susceptibility disorder characterized by multiple congenital abnormalities, progressive bone marrow failure, and cellular sensitivity to mitomycin C (MMC). FA has at least eight complementation groups (A, B, C, D1, D2, E, F, G), and six of the FA genes have been cloned. Several FA proteins, including FANCA, FANCC, FANCF, and FANCG, interact in a nuclear complex, and this complex is required for the activation (monoubiquitination) of the downstream FANCD2 protein. Activation of FANCD2 results in the assembly of FANCD2/BRCA1 foci. The aim of this study was to analyze the FA pathway in several FA patient-derived cell lines.
…, 1996
Hypersensitivity to cross-linking agents such as mitomycin C ("C) is characteristic of cells from patients suffering from the inherited bone marrow failure syndrome, Fanconi anemia (FA). Here, we link MMC hypersensitivity of Epstein-Barr virus (EBV)-immortalized FA lymphoblasts to a high susceptibility for apoptosis and p53 activation. In MMCtreated FA cells belonging to complementation group C (FA-C), apoptosis followed cell cycle arrest in the G2 phase. In stably transfected FA-C cells, plasmid-driven expression of the wild-type cytoplasmic FAC protein relieved MMC-dependent G2 arrest and suppressed p53 activation. However, in ANCON1 ANEMIA (FA) is an autosomal recessive disease characterized by developmental abnormalities (thumb and radius hypoplasia, microcephaly, growth delay, and kidney abnormalities), hyperpigmentation of the skin (cafk-au-lait spots), and life-threatening bone marrow failure.',' In addition, FA patients have a dramatically increased risk of developing malignancies, mainly acute myeloid leukemia and squamous cell carcinoma. Cultured FA cells exhibit an increased sensitivity to cross-linking agents such as mitomycin C ("C) and diepoxybutane.' Because of an increased level of spontaneous chromosomal aberrations in cultured cells, FA, like ataxia telangiectasia (AT) and Bloom syndrome (BS), is known as a chromosomal instability disorder. In FA, cell-fusion experiments have revealed four complementation groups, A to D'; recently, a fifth group was identified.4 In contrast to the UV-sensitivity diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, where disturbances in excision repair and transcription have been documented in detail,' the molecular bases of chromosomal instability disorders are still unknown. The FA group C gene, FAC (according to the nomenclature recommended by Lehmann et a16), cloned by Strathdee et al,7 is the first chromosomal instability disease gene isolated. The gene encodes a 63-kD polypeptide with no known sequence motifs that could provide a clue to its function. Since functionally active FAC protein apparently localizes to the cytoplasmic compartment of cells,8.' the protein is unlikely to be directly involved in DNA repair. Besides cross-linker hypersensitivity, cell cycle kinetic studies in primary fibroblasts and lymphocytes derived from FA patients revealed a characteristic spontaneous delay and arrest in G2."'.'' This phenomenon may explain the poor proliferative properties of primary FA cells. Since reduction F
The Fanconi Anemia Group C Gene Product Is Located in Both the Nucleus and Cytoplasm of Human Cells
Blood, 1998
The Fanconi anemia (FA) complementation group C (FAC) protein gene encodes a cytoplasmic protein with a predicted Mrof 63,000. The protein's function is unknown, but it has been hypothesized that it either mediates resistance to DNA cross-linking agents or facilitates repair after exposure to such factors. The protein also plays a permissive role in the growth of colony-forming unit–granulocyte/macrophage (CFU-GM), burst-forming unit–erythroid (BFU-E), and CFU-erythroid (CFU-E). Attributing a specific function to this protein requires an understanding of its intracellular location. Recognizing that prior study has established the functional importance of its cytoplasmic location, we tested the hypothesis that FAC protein can also be found in the nucleus. Purified recombinant Escherichia coli–derived FAC antigens were used to create antisera able to specifically identify an Mr = 58,000 protein in lysates from human Epstein-Barr virus (EBV)-transformed cell lines by immunoblot ana...
Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway
Human Molecular Genetics, 2001
Fanconi anaemia (FA) is an autosomal recessive inherited disorder associated with a progressive aplastic anaemia, diverse congenital abnormalities and cancer. The condition is genetically heterogeneous, with at least seven complementation groups (A-G) described. Cells from individuals who are homozygous for mutations in FA genes are characterized by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents. These features suggest a possible role for the encoded proteins in the recognition or repair of these lesions, but neither their function nor whether they operate in a concerted or discrete functional pathways is known. The recent cloning of the FANCF and FANCE genes has allowed us to investigate the interaction of the proteins encoded by five of the seven complementation groups of FA. We used the yeast twohybrid system and co-immunoprecipitation analysis to test the 10 possible pairs of proteins for direct interaction. In addition to the previously described binding of FANCA to FANCG, we now demonstrate direct interaction of FANCF with FANCG, of FANCC with FANCE and a weaker interaction of FANCE with both FANCA and FANCG. These findings show that the newly identified FANCE protein is an integral part of the FA pathway, and support the concept of a functional link between all known proteins encoded by the genes that are mutated in this disorder. These proteins may act either as a multimeric complex or by sequential recruitment of subsets of the proteins in a common pathway that protects the genomic integrity of mammalian cells.