Disease relevance of FANCA

• A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA [1].
• Unlike the lymphoblasts, this myeloid leukemia cell line (UoC-M1) was hypersensitive to mitomycin-C (MMC) and diepoxybutane (DEB) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L [2].
• Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia [2].
• Conversely, stable expression of FANCA mutants encoding intact FANCG interaction domains induced hypersensitivity to MMC in HeLa cells [3].
• We studied seven SNPs in FANCA, FANCL and FANCD2 in a total of 897 consecutive and non-related sporadic breast cancer cases and 1033 unaffected controls from the Spanish population [4].

Psychiatry related information on FANCA

• Because FA cells are sensitive to mitomycin C (MMC), FA gene products could be involved in cellular defense mechanisms [3].
• This study enables us to define this clinically heterogeneous disorder genotypically to better predict clinical outcome and aid decision-making regarding major therapeutic modalities for a subset of FA patients [5].
• Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439) [6].
• Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes [6].
• Pilots who attended FAA Safety Clinics tended to have a more internal locus of control than those who did not [7].

High impact information on FANCA

• Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers [8].
• The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC(1749T-->G, Leu496Arg) was altered by 1748C-->T, creating a cysteine codon [9].
• Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type [9].
• Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia (FA) patients resulting from compensatory secondary sequence alterations in cis [9].
• Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms including developmental anomalies, bone marrow failure and early occurrence of malignancies [10].

Chemical compound and disease context of FANCA

• A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA [11].
• FANCF-deregulated CC cell lines also exhibit a chromosomal hypersensitivity phenotype after exposure to an alkylating agent, a characteristic of FA patients [12].
• Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin [13].
• Fanconi anemia (FA) cells are hypersensitive to cytotoxicity, cell cycle arrest, and chromosomal aberrations induced by DNA cross-linking agents, such as mitomycin C (MMC) and nitrogen mustard (HN2) [14].
• The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells [15].

Biological context of FANCA

• The interaction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting [16].
• The G2/M checkpoint-mediated arrest of the cell cycle is critical for the prevention of both apoptosis and the accumulation of cells with rereplicated DNA, because the loss of ATR, BRCA1, or FANCA promotes apoptosis and suppresses the accumulation [17].
• The accumulation of cells with rereplicated DNA is restored by the artificial induction of a G2-phase arrest even when ATR, BRCA1, or FANCA is absent [17].
• All exons of FANCA and FANCG were sequenced, and no mutations were found [2].
• Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutations in the carboxy-terminal leucine zipper region, bound FANCG in the cytoplasm [18].

Anatomical context of FANCA

• To test directly the effect of this mutation on FANCA function, we used retroviral-mediated transduction to express either wild-type FANCA or FANCA(H1110P) protein in the FA-A fibroblast line, GM6914 [19].
• Studies using FANCA and FANCC knockout mice suggest that bone marrow precursors express interferon-gamma hypersensitivity and show progressive apoptosis [20].
• To elucidate the roles of FA genes in HR, we disrupted the FANCG/XRCC9 locus in the chicken B-cell line DT40 [21].
• Fanconi anemia (FA) is an autosomal recessively inherited disease with diverse clinical symptoms including developmental anomalies, predisposition to neoplasia, and a deficiency of hematopoietic stem cells resulting in progressive aplastic anemia [22].
• DNA extracted from individually plucked peripheral blood T cell colonies and marrow colony-forming unit granulocyte-macrophage and burst-forming unit erythroid cells revealed absence of the maternal FANCA exon 29 mutation in 74.0%, 80.3%, and 86.2% of colonies, respectively [23].

Associations of FANCA with chemical compounds

• However, these NES mutations did not affect the ability of FANCA to complement the mitomycin C or cisplatin sensitivity of FA-A lymphoblasts [24].
• Five functional leucine-rich nuclear export sequences (NESs) distributed throughout the FANCA sequence were identified and characterized using an in vivo export assay [24].
• After treatment with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export, the accumulation of epitope-tagged FANCA in the nucleus increased, whereas FANCC was affected to a lesser extent and FANCG showed no response [24].
• N-Ethylmaleimide treatment abolishes multimerization and interaction of FANCA and FANCG in vitro [25].
• Using DNA affinity chromatography, we now show that alphaSpIISigma, present in HeLa cell nuclei, specifically binds to DNA containing psoralen interstrand cross-links and that the FANCA, FANCC, and FANCG proteins are bound to this damaged DNA as well [26].

Physical interactions of FANCA

• We report that the protein encoded by the gene mutated in complementation group G (FANCG) localizes to the cytoplasm and nucleus of the cell and assembles in a molecular complex with the FANCA protein, both in vivo and in vitro [1].
• BRCA1 interacts directly with the Fanconi anemia protein FANCA [16].
• We demonstrate a direct interaction between FANCB and FANCL and that a complex of these proteins binds FANCA [27].
• FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins [28].
• Six of the eight proteins encoded by the known FA genes form a nuclear complex which is required for the monoubiquitination of the FANCD2 protein [29].

Regulatory relationships of FANCA

• The FA nuclear complex regulates the mono-ubiquitination of FANCD2 in response to DNA damage, resulting in targeting of this protein into nuclear foci [30].
• Both ATR and BRCA1 are required to activate the FA pathway [17].
• However, a high level of activation was found when FANCA was co-expressed with FANCG, indicating strong, direct interaction between these proteins [31].
• The observed specific changes in gene expression suggest that FANCC regulates specifically myeloid differentiation and unmasks a previously unsuspected anti-inflammatory role for the FA proteins [32].
• At present, it is poorly understood how the nuclear accumulation of FANCE is regulated and therefore we investigated the nuclear localization of this FA protein [33].

Other interactions of FANCA

• In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots) [34].
• Here we report the identification, by complementation cloning, of the gene mutated in FA complementation group E (FANCE) [35].
• Neither FANCA nor FANCC was found to interact with itself [36].
• Among the known FANC proteins, we find evidence for direct interaction only between the FANCA protein and BRCA1 [16].
• Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients [21].

Analytical, diagnostic and therapeutic context of FANCA

• Molecular cloning identified six causative genes (FANCA, -C, -D2, -E, -F, and -G) encoding a multiprotein complex whose precise biochemical function remains elusive [21].
• Site-directed mutagenesis of FANCA residues 18-29 revealed a novel arginine-rich interaction domain (RRRAWAELLAG) [3].
• The interaction between FANCA and SNX5 was confirmed by immunoprecipitation studies [37].
• DNA single-strand conformation polymorphism of each exon of the FANCA and FANCG genes was followed by sequence analysis of the aberrantly migrating fragments and by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the splice-site mutations identified [38].
• Sequence analysis of the FANCA gross deletion revealed recombination between two highly homologous Alu elements. cDNA analysis of the two splice mutations suggested intron 42 retention in FANCA IVS 42-2A>C and exon 4 skipping in FANCG IVS4+3A>G [38].

References