Seventy-five years ago, Dr. Guido Fanconi reported three siblings who exhibited both congenital defects and aplastic anemia.1 Since then, we have learned that Fanconi anemia (FA) is a rare multigenic disorder (a prevalence of 1-5 per million2), that predisposes children and adults to life-threatening bone marrow failure, myelodysplasia,3 acute nonlymphocytic leukemia (AML), and certain epithelial malignancies.4-7 So far, the sine qua non of this disease is cytogenetic instability in vitro after exposure of FA cells to bifunctional alkylating agents.8,9 Indeed, the current diagnostic test for Fanconi anemia, quantification of chromosomal breakage responses to alkylating agents, is based on this feature (reviewed in ref. 10). Classic clinical features such as growth retardation, small head size, café-au-lait spots, and radial ray defects can be strong diagnostic clues,11 but FA can occur in patients without congenital defects and can be clinically ascertained in adulthood. In fact, some patients with very minimal blood count abnormalities have been identified only because they were siblings of known FA patients and were tested for that reason. Consequently, there is substantial phenotypic heterogeneity in FA and while some of it can be explained by genetic heterogeneity, certain of the clinical consequences are the result of gene-environment interactions.
Somatic cell fusion studies have defined eleven complementation groups, FA-A, B, C, D1, D2, E, F, G, L, I and J.12 All eleven can be accounted for by mutations of a gene unique to that group and nine of the genes have been cloned13-15 (Table 1). Some of the proteins encoded by the normal FANC genes contain domains that suggest some functions (FANCG for example has a number of tetratricopeptide [TPR] repeats16). However, with the exception of FANCD1, now known to be identical to BRCA2,17 the genes and proteins they encode have no strong homologies to one another or to other known proteins.
Two recurring themes have emerged from published studies on the function of the FA proteins; (1) that they function to protect against genotoxic stress at least in part by forming complexes with each other and facilitating monoubiquitination of FANCD2, and (2) that the proteins also interact functionally with other proteins governing survival-signaling pathways.18 While this second function of FA proteins involves formation of complexes, they are probably complexes composed of molecules not found in the so called “core FA complex” that consists of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL. In fact, as will be mentioned in more detail below, the definition of the “core complex” is undergoing some substantial revision.
The FANC Genes
Reviewed below are selected features of each FANC gene and the proteins they encode. The chromosomal location and exon number of the genes and amino acid residues and molecular mass of the encoded proteins are listed in Table 1. A Fanconi Anemia Mutation Database, containing many FA mutations (but not all), is available (www.rockefeller.edu/fanconi/mutate). Currently, ascertainment of novel mutations is most often done by DHPLC analysis and sequencing of genomic DNA and cDNA. Apart from family studies, to confirm that an abnormality represents a mutation, complementation analysis (in which the wild type cDNA expressed in mutant cells corrects MMC/DEB sensitivity but the mutant cDNA does not) is most convincing. However, in light of the information now extant on key regions of FANC genes, some sequence variations (especially large deletions) can be assigned as mutations by deduction.
Mutations of this gene are by far the most common in patients with FA, accounting for 65% of all cases. The spectrum and scope of discrete mutations of this gene are immense and include nonsense, missense, and splicing mutations as well as microdeletions, microinsertions, and duplications.19 There may be more than 250 different mutant FANCA alleles, many of which are large intragenic deletions,20 and only a few are common especially c.1115_1118delTTGG (2% of FANCA alleles) and c.3788_3790delTCT (5% of FANCA alleles).19 The protein participates as a member of the core complex required for FANCD2 ubiquitination,21 and binds to BRCA1,22 but the functional role it plays in these complexes are unknown.
Post translational modifications of FANCA occur in response to environmental cues. For example, FANCA is redox-responsive and multimerizes with FANCG in response to oxidative stress.23 Phosphorylation of FANCA also occurs in normal cells but not in most FA cells. In vitro phosphorylation studies identified a cytoplasmic serine kinase embedded in the core complex (sensitive to wortmannin) that phosphorylated FANCA on serines.24 The functional consequences of this post-translational change and whether this putative FANCA kinase is the one that seems to be modulated by AKT25 are unknown.
Like FANCC, FANCA also seems to participate directly in support of survival signal transduction pathways. For example, FANCA interacts with IKK2 and may thereby integrate with the IkappaB kinase (IKK) signalsome in a functional way. Interestingly, this IKK2 interaction is reportedly required for stimulus-dependent phosphorylation of other proteins in the FA complex.26 FANCA also interacts with BRG1, a subunit of the SWI/SNF complex, and may regulate stress-induced chromatin remodeling.27 Intriguingly, in FANCA mutant cells the molecular chaperone GRP94 is found in a BRG-1 associated complex but is not found in normal or complemented cells.27 The significance of the phenomenon is unexplained but it is one of three specific examples in which aberrant or nonnative protein complexes are found in FA cells. In some instances (e.g., in the case of FANCC) there are aberrant signaling consequences that attend the formation of these complexes. Given that FANCA and FANCC both also associate with molecular chaperones,27-29 it is quite possible that these and other FA proteins are primarily cochaperones that maintain the proper structural conformation (and state of activation or inactivation) of proteins that protect cells from environmental stresses. This theoretical model would fit with every binding phenomenon and biological function assay described to date for the FA proteins. For example, the core complex could create a scaffold for the cross-linking agent-induced activation of an ubiquitin ligase (possibly FANCL).30
One of the most recently discovered FA genes was identified using a proteomics approach.31 FANCB was discovered by mass spectrometric analysis of a 95 kDa protein found in a multimeric FA complex. It has 10 exons, 7 of which are coding exons (3-10). The C terminus of the protein contains a putative bipartite nuclear localization signal and is present in nuclear extracts of normal cells but in mutant FA-A cells, FANCB is found, like FANCL, in the cytosol. That FANCB is required for FANCD2 monoubiquitination31 confirms that FANCB is a functional member of the core complex.
The gene encoding this protein is located at Xp22.31 and subject to X-chromosome inactivation. 31 In the cases described to date there are different mutations in this gene including insertional frameshifts in exon 3 and 8, a deletional frameshift in exon 8, and a large 5' and promoter deletion.31 It has been proposed that as a single active copy gene, the only X-linked FA gene, it may represent a vulnerability point for the genome of cells from obligate heterozygotes. An alternative view is that this protein too will prove to be multifunctional and required for cell survival. Indeed, studies of the methylation status of the gene showed that FANCB inactivation seems to be skewed toward the mutated allele.31
It is increasingly evident that the function of Fanconi proteins may be lost during multi-step carcinogenesis32-34 but it is not clear whether the loss occurs early or late in carcinogenesis. Based on serial studies of cytokine responses of committed hematopoietic progenitor cells in humans with FA,35 we have proposed that acquired loss of FA gene function cannot be an initiating event (such a cell would lose a competitive advantage) and that other somatic changes must occur first to protect such cells from the apoptotic consequences of FA loss.32,35,36 Two recent findings have supported this model indirectly. First, apoptotic responses are indeed blunted in marrow cells of FA knockout mice with clonal evolution.37,38 Second, the observation that in FANCB heterozygotes, X inactivation is skewed in favor of the mutated allele, indicates that the mutant cells are less fit to compete with the non mutant ones during development. A FANCB knockout mouse will be required to determine at which stage of development in heterozygotes the mutant FANCB cells are lost. There are likely other nonDNA damage related functions of the FANCB gene given that the affected males have classic FA phenotypes including bone marrow failure, but no data have been developed yet in support of this expectation.
This was the first of the FA genes to be cloned.13 Ten to fifteen percent of FA cases can be accounted for by mutations of this gene.39 Although there are a number of heterogeneous mutations of this gene, two mutations account for most of the known FANCC mutations; the first in exon 1 (322delG) and the other in exon 4 (c.711 + 4A>T, also until recently termed “IVS4+4A-T” is a single base change in the fourth intronic base that results in deletion of exon 4). The 322delG mutation is hypomorphic for some FANCC functions,40 likely because of a downstream reinitiation site that gives rise to a truncated protein.41 The c.711 + 4A>T is unique to patients of Ashkenazi Jewish ancestry in which population the carrier frequency is 1/100.42,43
Because it was the first gene cloned more is known about the function of FANCC than any other FA gene. Many of the lessons learned about this protein will likely hold generally for most of the other members of the core complex as well. FANCC is a member of the core complex,44-46 and binds to FANCE which facilitates nuclear translocation of FANCC.47,48 At least one nuclear function of this protein is to facilitate the FANCD2/BRCA1 interaction in S phase and in cells exposed to cross-linking agents. Another might be to influence cell cycle control because the FAC protein (but not a mutant protein) coimmunoprecipitates with cyclin-dependent kinase, cdc2.49 Other FANCC-interacting proteins are listed in Table 2.
FANCC Is Required for Survival of Hematopoietic Cells
In mice, the most consistent FA phenotype is hypogonadism,50-52 but in humans the single dominant early life-threatening feature of FA phenotype is hematopoietic failure that results from excessive apoptosis in hematopoietic cell populations including myeloid and erythroid progenitors.10,28,53-63 The FANCC protein sets a high apoptotic threshold in normal cells and apoptotic responses of FA cells exposed to certain extracellular apoptotic cues (interferon gamma, tumor necrosis factor alpha, mip-1α, fas ligand, and dsRNA) are exaggerated in vitro and in vivo.10,28,29,56,58,60,63-65
For the nuclear core FA complex to account for the hematopoiesis-specific anti-apoptotic function of FA proteins, it might serve to directly govern the expression of genes that encode intra- or extracellular survival factors specifically for hematopoietic cells. An alternative view, one better supported by experimental evidence, is that the FANC proteins have functions independent of their capacity to form “the nuclear core complex” and that some of the FA proteins might even work entirely on their own (see ref. 10).
FANCC and STAT Signaling
We determined more than a decade ago that FANCC is required for survival of hematopoietic cells.66 Our results predicted that the FANCC protein either facilitated survival signals or suppressed apoptotic cues. It turns out that FANCC plays both roles. For example, FANCC is required for optimal activation of STAT molecules and the Jak kinase family member Tyk2, thereby facilitating cell survival and preserving interferon responses,10,64 Recently it has been found that that the disruption of this signaling pathway underlies a subtle T-cell defect in Fancc knockout mice.67 The hematopoietic support function of CD4 cells is also perturbed (Fagerlie S, manuscript in preparation) emphasizing the multi-factorial nature of marrow failure in FA. That is, not only are myeloid and erythroid progenitor cells hypo-responsive to survival cues, lymphoid cells that support survival of progenitors are defective as well.
FANCC, hsp70, and PKR
FANCC also governs the apoptotic threshold by suppressing pro-apoptotic signals. It suppresses the state of activation of the double stranded RNA dependent protein kinase, PKR, by binding to hsp70 (like a cochaperone) and facilitating the association of PKR and hsp70.28,29,56 PKR exists in an inactive monomeric ground state in normal cells but is constitutively activated in FA-C cells.56 As a result of this aberrant state of activation of PKR, exposure of mutant cells to IFN-gamma and TNF-alpha hyper-activates PKR and accounts for earlier observations that FA-C progenitor cells were hypersensitive to IFN-gamma68 and TNF-alpha.58 Indeed, PKR activity is now known to be increased in primary bone marrow cells of patients with FA-C, FA-A, and FA-G.29,65 Interestingly, mutations of FANCC, FANCA and FANCG result in enhanced FANCC/PKR binding, and while it is unclear that this aberrant binding per se results in PKR activation (possibly by facilitating a structural change resulting in ground state PKR dimerization) the results do suggest that nonnative FA complexes can create serious pathophysiological consequences.65
FANCC and Oxidative Stress
It has become increasingly clear that the FA proteins play a role in controlling cellular responses to a variety of extracellular challenges and stress; biotic, oxidative, and chemical. Results of an ongoing multi-institutional FA transcriptome consortium support this notion. Results of the study will be broadly shared with the scientific community in 2005. There is also good biochemical evidence that FA proteins influence that states of activation of key mediators of cellular stress responses, including GSTP1 and ASK1.
Many investigators have long held that a fundamental defect of FA cells is intolerance to oxidative stress.69,70 In support of this notion, Buchwald's group recently reported that FANCC enhances the function of GSTP1 in cells exposed to inducers of apoptosis.54 GSTP1 is an enzyme that detoxifies by-products of redox stress and xenobiotics. While FANCC does not directly interact with GSTP1, its influence on this molecule may play a central role in tolerance of extracellular cues of many kinds. Haneline and her colleagues recently observed ASK1 hyper-activation in H2O2 -treated Fancc-/- cells and used gain- and loss-of-function analyses to confirm that the hypersensitivity of Fancc mutant cells to oxidative stress was mediated, at least in part, through altered redox regulation and ASK1 hyper activation.71
FANCC Is Multifunctional
Studies on STAT signaling defects in FA cells have also permitted the development of structure-function studies that prove that FANCC is multifunctional. Specifically, a central, highly conserved domain of FANCC is required for functional interaction with STAT1 and conservative mutations of this domain interfere with STAT signaling functions of FANCC but these mutations have no impact on the capacity of the domain mutant to complement in MMC assays.40 Another mutant (322delG) was unable to complement in MMC assays but did correct the STAT signaling defect. Interestingly, this mutation occurs in FA patients who have mild disease and mild hematopoietic defects.
Studies on FANCC and the Molecular Basis of Mosaicism
Some patients with FA exhibit mosaicism in hematopoietic cells. These cases are ascertained by observing 2 subpopulations of lymphocytes, one sensitive and one resistant to cross-linking agents. Studies on FANCC structure have revealed mechanisms by which mosaicism occurs in such patients and can be used as a model for mosaicism in other complementation groups. Mosaicism can derive from recombination72 or compensatory sequence alterations in cis.73 Two patterns of recombination were described in haplotype analyses;72 the first was a single intragenic crossover between the maternally and paternally inherited mutations and the second was likely gene conversion. In support of the hematopoietic survival function of FANCC, in the majority of the mosaic patients studied, the blood counts were only minimally suppressed.72
In summary, FANCC is a multifunctional protein that protects cells from the genotoxic consequences of cross-linking agent exposure by complexing with other members of the FA core complex to participate in the “linear pathway”.21 It also supports survival of cells in the ground state and cells exposed to a variety of biological cues that induce apoptotic responses. It does this by participating in at least three signaling pathways (STAT, PKR, and ASK signaling) at least in part by functioning very much in the same way a cochaperone would function. We believe that in time these nongenotoxicity functions of FANCC will be matched by like functions of the other FA proteins, some of which have domains (e.g., the TPR motifs in FANCG) that theoretically meet standards for cochaperone functionality.74-76
Two observations converged to reveal the identity of the FANCD1 gene. First, it was known that BRCA2 binds Rad51,77,78 and second that FANCD1 mutant cells exhibited aberrant damage-induced Rad51 nuclear focus formation.79 These observations led to identification of BRCA2 as a FA-D1 complementing gene17 and the confirmation that FA alleles of BRCA2 disrupt the Rad51 binding region.80 This is not a common allele and because truly null mutations of BRCA2 are lethal in a murine model,81 the mutations of BRCA2 that lead to FA are likely hypomorphic. The few FA-D1 patients identified to date have presented with early-onset malignancies of both hematopoietic and nonhematologic types.82
Monoubiquitinated FANCD2 seems to promote loading of BRCA2 into multimeric complexes on chromatin by binding to the C terminus of BRCA2.83 Two separate sites on BRCA2 also interact with FANCG.84 Using the I-SceI endonuclease to introduce a double-strand break at a specific chromosomal locus, Jasin's group found that BRCA2 mutant cell lines are recombination deficient.85 Therefore, it is likely that these complexes are required for normal homology-directed DNA repair.
The gene cloned by Markus Grompe's group at Oregon Health and Science University86 led to the development of the “linear pathway model” for integration of FA protein function. FANCD2 associates with RAD51 and BRCA1 during S phase87 but given the sheer size and likely complexity of these multimeric complexes, the association of these proteins per se is not sufficient to facilitate DNA repair by homologous recombination. Ubiquitination of FANC2 requires the core complex but efficient ubiquitination also requires the ATR checkpoint kinase and RPA1.88 Recently the deubiquitinating enzyme, USP1 was found to bind to FANCD2 (Table 2) and suppress expression of the ubiquitinated form.89
There is a good deal of uncertainty about the function of the monoubiquitinated form of FANCD2 and its functional relationship with BRCA1 and BRCA2. For example, there were conflicting reports on the influence of the FA pathway on Rad51 and BRCA2 focus formation in cells exposed to ionizing radiation. Ohashi et al90 recently utilized BRCA2 and FANCD2 deficient cells and cells treated with siRNAs specifically targeting BRCA2, Rad51, and FANCD2 and developed data suggesting that FANCD2 does not have a direct role in BRCA2 and Rad51 associated homologous recombination repair after DNA damage.
This question still requires further evaluation because (1) survival assays were utilized (2) FA cells are hypersensitive to interferon (3) of the known capacity of some siRNAs to activate interferon responses,91 and this pitfall was not experimentally ruled out.
FANCD2 and Diagnosis of Fanconi Anemia
Inactivating mutations in all FA genes but BRCA2 lead to failure of accumulation of FANCD2 in damage-induced nuclear foci21 and FANC alleles of BRCA2 interdict accumulation of Rad51 in such foci.79 Therefore, although it is currently impractical, screening cells for FA lesions could involve microscopic assessments of damage-induced nuclear foci for FANCD2 and Rad51. FANCD2 immunoblots that distinguish the ubiquitinylated and nonubiquitinylated forms of FANCD2 might also be used to implicate inactivating mutations of any known FA gene except BRCA2.92 In the context of an unambiguous FA phenotype (by MMC assays in the appropriate clinical setting), if FANCD2 is ubiquitinylated the likely complementation groups would be FA-D1 or FA-J. BRCA2 mutants could be then identified using BRCA2 immunoblots which should reveal only truncated versions of the protein.
A rare FA gene, FANCE maps to 6p22-p2193 and encodes a 536 amino acid protein that is part of the core complex15,94 but plays a role in transporting cytoplasmic FANCC into the nucleus.48 Mutations of FANCE include a 355C-T transition in the FANCE gene, leading to a gln119-to-ter (Q119X) nonsense change, a G-to-A change at position -8 in intron 5, resulting in false splicing and insertion of 6 nucleotides from intron 5, including an in-frame stop codon, and a 421C-T transition resulting in an arg141-to-ter (R141X) nonsense change.15
Discovered by complementation cloning, de Winter et al found that the FANCF gene is intronless and encoded a peptide with homology to the N terminus (RNA binding domain) of the prokaryotic RNA-binding protein ROM.14 FANCF is largely nuclear and is a member of the core complex. Mutations of FANCF described to date are mostly deletions including a 23 base-pair deletion of nucleotides 230-252, a 47-bp deletion (349-395), a 2 bp deletion (484-485). Other mutations include a 16C-T transition resulting in a gln6-to-ter nonsense mutation, and a 327C-G transversion (yr109-to-ter nonsense mutation).
The protein encoded by this gene may function as a super-scaffold, organizing the formation of multimeric FA complexes. The C-terminus of FANCF interacts directly with FANCG and may facilitate the assembly of other FA proteins into the core complex (or other complexes for that matter).95 The N-terminus of FANCF seems to stabilize the FANCA/FANCG interaction and is also required for binding of the FANCC/FANCE complex.95
By functional complementation of the Chinese Hamster ovarian cell line UV40, Liu et al96 cloned XRCC9 a gene that conferred resistance to both hygromycin and mitomycin C. Later FANCG was shown to be identical to XRCC997 which had been localized to 9p13. The putative 622-amino acid nuclear and cytoplasmic protein is a member of the core complex46,98 and is phosphorylated at serines 7, 385 and 387.99-101
Survival signaling functions of FANCG involve suppression by (in collaboration with FANCC and FANCA) of the proapoptotic double stranded RNA-dependent protein kinase PKR.65 In FANCG mutant cells, binding of FANCC and PKR is increased.65 In keeping with the theme that nonnative interactions of FA proteins with signaling proteins in FA mutant cells contribute to pathogenesis, PKR activity is increased in bone marrow cells of patients with Fanconi anemia with mutations in the FANCC, FANCA, and FANCG genes.
There are numerous FANCG mutations. Most result in protein truncations102 but the sites of mutation are not clustered. In 9 German FAG patients there was a 313G-T transversion in 8 of 18 (44%) mutated alleles.102 In 7 Portuguese-Brazilian probands Auerbach et al103 reported IVS8AS-2A-G. The same team also reported IVS11DS+1G-C in 7 French-Acadian probands, 1794-1803del in 7 European probands, and IVS3+1G>C (five Korean or Japanese probands) and suggest that the Portuguese-Brazilian, French-Acadian, and Korean/Japanese mutations were likely to have been present in a founding member of each of these populations. In black populations of sub-Saharan Africa, the incidence of FA is >1/40,000 and 82% of cases carry the same FANCG mutation (c.637_643 del TACCGCC).104
FANCG protein is a member of the core complex, associates with FANCA and FANCF, and dimerizes with FANCA in cells exposed to oxidative stress.23 FANCG has 6 or 7 (depending on the stringency of the consensus sequence definition) tetratricopeptide repeats,16 elements that facilitate protein-protein interactions and, interestingly, are domains used by other cochaperones to bind to hsc70105 and hsp90,76,106,107 raising the distinct possibility that FANCG, like FANCC may integrate with heat shock responses as a cochaperone.
There is no FANCH gene. It was predicted from complementation group analysis carried out on cells later shown to be FANCA mutants.108
FANCI and FANCJ
Neither of these two recently identified genes has been cloned to date. That they exist is suggested by somatic cell fusion/complementation analyses and/or genetic data.12 Using immunoblot analyses for FA core complex formation and FANCD2 mono-ubiquitination, Levitus et al demonstrated that both FA-I and FA-J cell lines formed a core complex, that FA-I cells were not capable of ubiquitinating FANCD2, and that FA-J cells did ubiquitinate FANCD2.12 This placed the theoretical protein encoded by the mutated gene in FA-J cells “downstream” of the FANCD2 ubiquitination step.
This was the first of two FA genes (FANCB being the other) identified using a proteomics approach. Specifically, Meetei et al30 identified, using mass spectrometry, a 43 kDal Fanconi complex associated protein as PHD finger protein-9 (PHF9). The 373-amino acid protein contains 3 WD40 repeats and a PHD-type zinc finger motif and is clearly a key component of the FA core complex. The protein has ubiquitin ligase activity and may play an important role in the monoubiquitylation of FANCD2.109 In effect, the other members of the core complex may serve as a scaffold that permits the presentation of FANCL to FANCD2 and possibly to other proteins as well. In fact, taking into account the degree to which FANCD2 is conserved throughout evolution86 it seems not sufficiently parsimonious that a complex of 7 FA proteins has evolved simply to facilitate one post translational change of FANCD2. Experiments are now underway in our laboratory to identify other substrates that might be ubiquitinated by the FA complex.
The mutation described by Meetei et al30 was a deletion of exon 11 that removed the part of the WD40 repeat and the entire conserved PHD finger. It arose by homozygous insertion of 177bp at the intron 10/exon 11 splice junction.
FA Protein Complexes
The FA “Nuclear Core Complex”
With the exception of FANCD2 and BRCA2, most of the FA proteins are thought to form a large multi-protein complexes.21,110-114 Inactivating mutations of FANCA, FANCB, FANCC, FANCE and FANCG proteins reduce assembly, stability, and/or nuclear translocation of the multi-subunit FA protein “core” complex.46,114
One function of the core complex has been deduced by nicely-designed studies on isogenic FA mutant cell lines. These studies have clarified an emerging relationship between FANC proteins and some functions of BRCA1, BRCA2 and Rad51. First, as mentioned above, certain BRCA2 (FANCD1) mutations can result in the FA phenotype (FA-D1)17 and the mutations result in failure of Rad51 to localize in damage-induced nuclear foci.79 Second, it seems clear that inactivation of any one of the core complex proteins interdicts formation of the complete FA complex, one consequence of which is reduced ubiquitinylation and BRCA1-colocalizing capacity of the nuclear FA protein FANCD2.21 Therefore, accumulation of BRCA1 and Rad51 in damage-induced nuclear foci is required to protect cells from damage induced by cross-linking agents. Moreover, to accumulate in these foci, BRCA1 requires FANCA, B, C, G, and F dependent monoubiquitination of FANCD2.
What else might the FA complexes do in normal cells? Clearly the complex associates with chromatin in S-phase44 and while there is no biochemical evidence that this is linked with a repair function, it is an appealing assumption in view of the importance of homologous recombination repair in S phase.115,116 It is also specifically appealing in light of the linkage between the BRCA1/2 pathways and the FA pathway.
FA proteins, BRCA1, and BRCA2 are known to protect cells from cross-linking agent and oxidation induced genotoxicity.77,79,85,117-119 Other proteins function in these ways as well, including ATR, Mre11, Tip60, NBS1, Rad51, Rad54, Rev3, Snm1, XRCC2, XRCC3, ERCC1, BLM, and Xpf, although none are associated with the disease Fanconi anemia. However, the precise biochemical functions of the FA complexes are unclear. Based on the current literature, it seems most likely that the FA proteins create scaffolds for assembly and proper folding of enzymes and multimeric complexes and that the client substrates of the FA proteins each function to protect the genome and set thresholds for responses to apoptotic cues. It is widely expected that these proteins are effectors of DNA repair (because of their known function in transcription coupled and homologous recombination repair,85,117,120) but biochemical studies have yet to confirm this. Moreover, as a reasonable parallel model, the BRCA1 and BRCA2 proteins exhibit other activities than their role in modulation of genotoxicity. They directly participate in transcriptional control,121-125 cytoplasmic signal transduction,126 and regulation of differentiation.124,127 More work needs to be done to clarify the FA-BRCA1 relationships in functional terms.
The components of the FA complexes are increasing in number as it becomes clear that there is variability from method-to-method and from one subcellular compartment to another. Formation of complexes is a dynamic process that can be influenced by cell cycle phase, or by chemical or biological cues. Using chromatographic analyses Kupfer's group discovered that the FA “core complex” varies between subcellular compartments. The FA core complex exists in a 500-600 kDal cytoplasmic form, a larger 750 kDal cytoplasmic form seen only in mitosis, a 2 MDal nuclear form, and a 1 MDal form bound to chromatin.45 Interestingly, monoubiquitinated FANCD2 and BRCA2 also interact in chromatin fractions,83 but because BRCA2 dependent RAD51 nuclear focus formation can occur independently of FANCD2,90 the function of the D2/BRCA2 complex may have nothing to do with Rad51 focus formation.
As has been described above, the tendency of FA proteins to form large multimeric complexes has been exploited investigatively to discover new FA proteins. Using a global immunoprecipitation method, Meetei et al128 identified 3 distinct multiprotein complexes associated with the Bloom's protein, BLM. One of these (“BRAFT”) contained topoisomerase III-alpha, replication protein A and the core complex FA proteins. Other members of the complex ultimately proved to be FANCB and FANCL.30,31
In summary, most of the FA genes have been cloned now and the elucidation of the FA nuclear complex model by Garcia-Higuera et al21,46,129 has been extraordinarily helpful in describing a unified vision of how mutations of these disparate proteins can lead to the same aberrant response to MMC. There is also a good deal of evidence that separate functions of the FA proteins account for the molecular pathogenesis of the hematopoietic defects and carcinogenesis but it is less clear whether these functions require participation of the other FA proteins or not. The most coherent functional view of FA proteins is that they act as cochaperones creating multimeric scaffolds that set response thresholds for environmental stress. In view of the emerging evidence that FA proteins affiliate with critically important tumor suppressor genes on the one hand, and participate in survival signaling pathways in hematopoietic cells on the other, studies on the function of these gene products have exciting promise for investigators interested in mammalian development, responses to biotic stress, carcinogenesis, hematopoietic control, and the immune response.
- Fanconi G. Familiare infantile perniziosaartige anaemia (pernizioses blutbild und konstitution) Jahrb Kinderhilkd. 1927;117:257–280.
- Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet. 2001;2(6):446–459. [PubMed: 11389461]
- Alter BP, Caruso JP, Drachtman RA. et al. Fanconi anemia: Myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet. 2000;117(2):125–131. [PubMed: 10704682]
- Rosenberg PS, Socie G, Alter BP. et al. Risk of head and neck squamous cell cancer and death in transplanted and untransplanted patients with fanconi anemia. Blood. 2004 [PubMed: 15331448]
- Auerbach AD, Allen RG. Leukemia and preleukemia in Fanconi anemia patients: A review of the literature and report of the International Fanconi Anemia Registry. Cancer Genet Cytogenet. 1991;51:1–12. [PubMed: 1984836]
- Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer. 2003;97(2):425–440. [PubMed: 12518367]
- Alter BP. Fanconi's anemia and malignancies. Am J Hematol. 1996;53(2):99–110. [PubMed: 8892734]
- Sasaki MS, Tonomura A. A high susceptibility of Fanconi's anemia to chromosome breakage by DNA cross-linking agents. Cancer Res. 1973;33(8):1829–1836. [PubMed: 4352739]
- Auerbach AD, Adler B, Chaganti RS. Prenatal and postnatal diagnosis and carrier detection of Fanconi anemia by a cytogenetic method. Pediatrics. 1981;67:128–135. [PubMed: 7243421]
- Fagerlie S, Lensch MW, Pang Q. et al. The Fanconi anemia group C gene product. Signaling functions in hematopoietic cells. Exp Hematol. 2001;29(12):1371–1381. [PubMed: 11750095]
- Bagby GC, Lipton JM, Sloand EM. et al. Marrow failure. Hematology Am Soc Hematol Educ Program. 2004:318–336. [PubMed: 15561690]
- Levitus M, Rooimans MA, Steltenpool J. et al. Heterogeneity in Fanconi anemia: Evidence for 2 new genetic subtypes. Blood. 2004;103(7):2498–2503. [PubMed: 14630800]
- Strathdee CA, Gavish H, Shannon WR. et al. Cloning of cDNAs for Fanconi's anaemia by functional complementation. Nature. 1992;356:763–767. [PubMed: 1574115]
- de WinterJP, Rooimans MA, van Der WL. et al. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nat Genet. 2000;24(1):15–16. [PubMed: 10615118]
- de WinterJP, Leveille F, van Berkel CG. et al. Isolation of a cDNA representing the Fanconi anemia complementation group E gene. Am J Hum Genet. 2000;67(5):1306–1308. [PMC free article: PMC1288571] [PubMed: 11001585]
- Blom E, van de Vrugt HJ, Vries Y. et al. Multiple TPR motifs characterize the Fanconi anemia FANCG protein. DNA Repair (Amst) 2004;3(1):77–84. [PubMed: 14697762]
- Howlett NG, Taniguchi T, Olson S. et al. Biallelic Inactivation of BRCA2 in Fanconi Anemia. Science. 2002 [PubMed: 12065746]
- Bagby JrGC. Genetic basis of Fanconi anemia. Curr Opin Hematol. 2003;10(1):68–76. [PubMed: 12483114]
- Levran O, Diotti R, Pujara K. et al. Spectrum of sequence variations in the FANCA gene: An International Fanconi Anemia Registry (IFAR) study. Hum Mutat. 2005;25(2):142–149. [PubMed: 15643609]
- Morgan NV, Tipping AJ, Joenje H. et al. High frequency of large intragenic deletions in the Fanconi anemia group A gene. Am J Hum Genet. 1999;65(5):1330–1341. [PMC free article: PMC1288285] [PubMed: 10521298]
- Garcia-Higuera I, Taniguchi T, Ganesan S. et al. Interaction of the Fanconi Anemia Proteins and BRCA1 in a Common Pathway. Mol Cell. 2001;7(2):249–262. [PubMed: 11239454]
- Folias A, Matkovic M, Bruun D. et al. BRCA1 interacts directly with the Fanconi anemia protein FANCA. Hum Mol Genet. 2002;11(21):2591–2597. [PubMed: 12354784]
- Park SJ, Ciccone SLM, Beck BD. et al. Oxidative stress/damage induces multimerization and interaction of Fanconi anemia proteins. Journal of Biological Chemistry. 2004;279(29):30053–30059. [PubMed: 15138265]
- Yagasaki H, Adachi D, Oda T. et al. A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA. Blood. 2001;98(13):3650–3657. [PubMed: 11739169]
- Otsuki T, Nagashima T, Komatsu N. et al. Phosphorylation of Fanconi anemia protein, FANCA, is regulated by Akt kinase. Biochem Biophys Res Commun. 2002;291(3):628–634. [PubMed: 11855836]
- Otsuki T, Young DB, Sasaki DT. et al. Fanconi anemia protein complex is a novel target of the IKK signalsome. J Cell Biochem. 2002;86(4):613–623. [PubMed: 12210728]
- Otsuki T, Furukawa Y, Ikeda K. et al. Fanconi anemia protein, FANCA, associates with BRG1, a component of the human SWI/SNF complex. Hum Mol Genet. 2001;10(23):2651–2660. [PubMed: 11726552]
- Pang Q, Keeble W, Christianson TA. et al. FANCC interacts with hsp70 to protect hematopoietic cells from IFNg/TNFa- mediated cytotoxicity. EMBO J. 2001;20(16):4478–4489. [PMC free article: PMC125562] [PubMed: 11500375]
- Pang QS, Christianson TA, Keeble W. et al. The anti-apoptotic function of Hsp70 in the interferon-inducible double-stranded RNA-dependent protein kinase-mediated death signaling pathway requires the Fanconi anemia protein, FANCC. Journal of Biological Chemistry. 2002;277(51):49638–49643. [PubMed: 12397061]
- Meetei AR, de WinterJP, Medhurst AL. et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat Genet. 2003;35(2):165–170. [PubMed: 12973351]
- Meetei AR, Levitus M, Xue Y. et al. X-linked inheritance of Fanconi anemia complementation group B. Nat Genet. 2004;36(11):1219–1224. [PubMed: 15502827]
- Lensch MW, Tischkowitz M, Christianson TA. et al. Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. Blood. 2003;102(1):7–16. [PubMed: 12637330]
- Couch FJ, Johnson MR, Rabe K. et al. Germ line Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res. 2005;65(2):383–386. [PubMed: 15695377]
- Taniguchi T, Tischkowitz M, Ameziane N. et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med. 2003;9(5):568–574. [PubMed: 12692539]
- Lensch MW, Rathbun RK, Olson SB. et al. Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: A view from the window of Fanconi anemia. Leukemia. 1999;13(11):1784–1789. [PubMed: 10557053]
- Bagby GC, Olson SB. Cisplatin and the sensitive cell. Nat Med. 2003;9(5):513–514. [PubMed: 12724761]
- Haneline LS, Li X, Ciccone SL. et al. Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc -/- hematopoietic stem cells and decreases the risk of clonal evolution. Blood. 2002 [PubMed: 12393504]
- Li X, Le BeauMM, Ciccone S. et al. Ex vivo culture of Fancc -/- stem/ progenitor cells predisposes cells to undergo apoptosis and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy Blood 2005. (in press) [PMC free article: PMC1895016] [PubMed: 15644418]
- Gibson RA, Morgan NV, Goldstein LH. et al. Novel mutations and polymorphisms in the Fanconi anemia group C gene. Hum Mutat. 1996;8(2):140–148. [PubMed: 8844212]
- Pang Q, Christianson TA, Keeble W. et al. The Fanconi anemia complementation group C gene product: Structural evidence of multifunctionality. Blood. 2001;98(5):1392–1401. [PubMed: 11520787]
- Yamashita T, Wu N, Kupfer G. et al. Clinical variability of fanconi anemia (type C) results from expression of an amino terminal truncated fanconi anemia complementation group C polypeptide with partial activity. Blood. 1996;87:4424–4432. [PubMed: 8639804]
- Whitney MA, Jakobs P, Kaback M. et al. The Ashkenazi Jewish Fanconi anemia mutation: Incidence among patients and carrier frequency in the at-risk population. Hum Mutat. 1994;3:339–341. [PubMed: 8081385]
- Kutler DI, Auerbach AD. Fanconi anemia in Ashkenazi Jews. Fam Cancer. 2004;3(3-4):241–248. [PubMed: 15516848]
- Mi J, Kupfer GM. The fanconi anemia core complex associates with chromatin during s phase. Blood. 2004 [PubMed: 15256425]
- Thomashevski A, High AA, Drozd M. et al. The Fanconi anemia core complex forms 4 different sized complexes in different subcellular compartments. J Biol Chem. 2004 [PubMed: 15082718]
- Garcia-Higuera I, Kuang Y, Naf D. et al. Fanconi anemia proteins FANCA, FANCC, and FANCG/ XRCC9 interact in a functional nuclear complex. Mol Cell Biol. 1999;19(7):4866–4873. [PMC free article: PMC84285] [PubMed: 10373536]
- Gordon SM, Buchwald M. The Fanconi anemia protein complex: Mapping protein interactions in the yeast two- and three-hybrid systems. Blood. 2003;102(1):136–141. [PubMed: 12649160]
- Taniguchi T, D'Andrea AD. The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC. Blood. 2002;100(7):2457–2462. [PubMed: 12239156]
- Kupfer GM, Yamashita T, Naf D. et al. The Fanconi anemia polypeptide, FAC, binds to the cyclin- dependent kinase, cdc2. Blood. 1997;90:1047–1054. [PubMed: 9242535]
- Nadler JJ, Braun RE. Fanconi anemia complementation group C is required for proliferation of murine primordial germ cells. Genesis. 2000;27(3):117–123. [PubMed: 10951504]
- Cheng NC, van de Vrugt HJ, Van der Valk MA. et al. Mice with a targeted disruption of the Fanconi anemia homolog Fanca. Hum Mol Genet. 2000;9(12):1805–1811. [PubMed: 10915769]
- Koomen M, Cheng NC, van de Vrugt HJ. et al. Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice. Hum Mol Genet. 2002;11(3):273–281. [PubMed: 11823446]
- Cumming RC, Liu JM, Youssoufian H. et al. Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene. Blood. 1996;88(12):4558–4567. [PubMed: 8977247]
- Cumming RC, Lightfoot J, Beard K. et al. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat Med. 2001;7(7):814–820. [PubMed: 11433346]
- Maciejewski JP, Selleri C, Sato T. et al. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol. 1995;91:245–252. [PubMed: 7577642]
- Pang Q, Keeble W, Diaz J. et al. Role of double-stranded RNA-dependent protein kinase in mediating hypersensitivity of Fanconi anemia complementation group C cells to interferon gamma, tumor necrosis factor-alpha, and double-stranded RNA. Blood. 2001;97(6):1644–1652. [PubMed: 11238103]
- Wang J, Otsuki T, Youssoufian H. et al. Overexpression of the Fanconi anemia group C gene (FAC) protects hematopoietic progenitors from death induced by Fas-mediated apoptosis. Cancer Res. 1998;58(16):3538–3541. [PubMed: 9721856]
- Otsuki T, Nagakura S, Wang J. et al. Tumor necrosis factor-alpha and CD95 ligation suppress erythropoiesis in Fanconi anemia C gene knockout mice. J Cell Physiol. 1999;179(1):79–86. [PubMed: 10082135]
- Fagerlie SR, Diaz J, Christianson TA. et al. Functional correction of FA-C cells with FANCC suppresses the expression of interferon gamma-inducible genes. Blood. 2001;97(10):3017–3024. [PubMed: 11342426]
- Haneline LS, Broxmeyer HE, Cooper S. et al. Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from FAC -/- mice. Blood. 1998;91:4092–4098. [PubMed: 9596654]
- Koh PS, Hughes GC, Faulkner GR. et al. The Fanconi anemia group C gene product modulates apoptotic responses to tumor necrosis factor-α and Fas ligand but does not suppress expression of receptors of the tumor necrosis factor receptor superfamily. Exp Hematol. 1999;27(1):1–8. [PubMed: 9923438]
- Li Y, Youssoufian H. MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups. J Clin Invest. 1997;100(11):2873–2880. [PMC free article: PMC508494] [PubMed: 9389754]
- Rathbun RK, Faulkner GR, Ostroski MH. et al. Inactivation of the Fanconi anemia group C (FAC) gene augments interferon-gamma-induced apoptotic responses in hematopoietic cells. Blood. 1997;90:974–985. [PubMed: 9242526]
- Pang Q, Fagerlie S, Christianson TA. et al. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Mol Cell Biol. 2000;20(13):4724–4735. [PMC free article: PMC85895] [PubMed: 10848598]
- Zhang XL, Li J, Sejas DP. et al. The Fanconi anemia proteins functionally interact with the protein kinase regulated by RNA (PKR) Journal of Biological Chemistry. 2004;279(42):43910–43919. [PubMed: 15299030]
- Segal GM, Magenis RE, Brown M. et al. Repression of Fanconi anemia gene (FACC) expression inhibits growth of hematopoietic progenitor cells. J Clin Invest. 1994;94(2):846–852. [PMC free article: PMC296166] [PubMed: 7518843]
- Fagerlie SR, Koretsky T, Torok-Storb B. et al. Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice. Journal of Immunology. 2004;173(6):3863–3870. [PubMed: 15356134]
- Whitney MA, Royle G, Low MJ. et al. Germ cell defects and hematopoietic hypersensitivity to g-interferon in mice with a targeted disruption of the Fanconi anemia C gene. Blood. 1996;88:49–58. [PubMed: 8704201]
- Pagano G. Mitomycin C and diepoxybutane action mechanisms and FANCC protein functions: Further insights into the role for oxidative stress in Fanconi's anaemia phenotype. Carcinogenesis. 2000;21(5):1067–1068. [PubMed: 10783335]
- Clarke AA, Philpott NJ, Gordon-Smith EC. et al. The sensitivity of Fanconi anaemia group C cells to apoptosis induced by mitomycin C is due to oxygen radical generation, not DNA crosslinking. Br J Haematol. 1997;96(2):240–247. [PubMed: 9029006]
- Saadatzadeh MR, Bijangi-Vishehsaraei K, Hong P. et al. Oxidant hypersensitivity of Fanconi anemia type C deficient cells is dependent on a redox-regulated apoptotic pathway. J Biol Chem. 2004 [PubMed: 14764578]
- Lo Ten Foe JR, Kwee ML, Rooimans MA. et al. Somatic mosaicism in Fanconi anemia: Molecular basis and clinical significance. Eur J Hum Genet. 1997;5:137–148. [PubMed: 9272737]
- Waisfisz Q, Morgan NV, Savino M. et al. Spontaneous functional correction of homozygous Fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet. 1999;22(4):379–383. [PubMed: 10431244]
- Brinker A, Scheufler C, Von Der MF. et al. Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70 x Hop x Hsp90 complexes. J Biol Chem. 2002;277(22):19265–19275. [PubMed: 11877417]
- Chen S, Sullivan WP, Toft DO. et al. Differential interactions of p23 and the TPR-containing proteins Hop, Cyp40, FKBP52 and FKBP51 with Hsp90 mutants. Cell Stress Chaperones. 1998;3(2):118–129. [PMC free article: PMC312955] [PubMed: 9672247]
- Prodromou C, Siligardi G, O'Brien R. et al. Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain cochaperones. EMBO J. 1999;18(3):754–762. [PMC free article: PMC1171168] [PubMed: 9927435]
- Davies AA, Masson J, McIlwraith MJ. et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 2001;7(2):273–282. [PubMed: 11239456]
- Marmorstein LY, Ouchi T, Aaronson SA. The BRCA2 gene product functionally interacts with p53 and RAD51. Proc Natl Acad Sci USA. 1998;95(23):13869–13874. [PMC free article: PMC24938] [PubMed: 9811893]
- Godthelp BC, Artwert F, Joenje H. et al. Impaired DNA damage-induced nuclear Rad51 foci formation uniquely characterizes Fanconi anemia group D1. Oncogene. 2002;21(32):5002–5005. [PubMed: 12118380]
- Stewart G, Elledge SJ. The two faces of BRCA2, a FANCtastic discovery. Mol Cell. 2002;10(1):2–4. [PubMed: 12150898]
- Ludwig T, Chapman DL, Papaioannou VE. et al. Targeted mutations of breast cancer susceptibility gene homologs in mice: Lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/ p53 nullizygous embryos. Genes Dev. 1997;11(10):1226–1241. [PubMed: 9171368]
- Hirsch B, Shimamura A, Moreau L. et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004;103(7):2554–2559. [PubMed: 14670928]
- Wang X, Andreassen PR, D'Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004;24(13):5850–5862. [PMC free article: PMC480901] [PubMed: 15199141]
- Hussain S, Witt E, Huber PAJ. et al. Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1. Hum Mol Genet. 2003;12(19):2503–2510. [PubMed: 12915460]
- Moynahan ME, Pierce AJ, Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001;7(2):263–272. [PubMed: 11239455]
- Timmers C, Taniguchi T, Hejna J. et al. Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell. 2001;7(2):241–248. [PubMed: 11239453]
- Taniguchi T, Garcia-Higuera I, Andreassen PR. et al. S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood. 2002;100(7):2414–2420. [PubMed: 12239151]
- Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004;18(16):1958–1963. [PMC free article: PMC514175] [PubMed: 15314022]
- Nijman SM, Huang TT, Dirac AM. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005;17(3):331–339. [PubMed: 15694335]
- Ohashi A, Zdzienicka MZ, Chen J. et al. FANCD2 functions independently of BRCA2 and RAD51 associated homologous recombination in response to DNA damage. J Biol Chem. 2005 [PubMed: 15671039]
- Sledz CA, Holko M, de Veer MJ. et al. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol. 2003;5(9):834–839. [PubMed: 12942087]
- Shimamura A, Montes DO, Svenson JL. et al. A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood. 2002;100(13):4649–4654. [PubMed: 12393398]
- Waisfisz Q, Saar K, Morgan NV. et al. The Fanconi anemia group E gene, FANCE, maps to chromosome 6p. Am J Hum Genet. 1999;64(5):1400–1405. [PMC free article: PMC1377877] [PubMed: 10205272]
- Pace P, Johnson M, Tan WM. et al. FANCE: The link between Fanconi anaemia complex assembly and activity. EMBO J. 2002;21(13):3414–3423. [PMC free article: PMC125396] [PubMed: 12093742]
- Léveillé F, Blom E, Medhurst AL. et al. The Fanconi anemia gene product FANCF is a flexible adaptor protein. Journal of Biological Chemistry. 2004;279(38):39421–39430. [PubMed: 15262960]
- Liu N, Lamerdin JE, Tucker JD. et al. The human XRCC9 gene corrects chromosomal instability and mutagen sensitivities in CHO UV40 cells. Proc Natl Acad Sci USA. 1997;94(17):9232–9237. [PMC free article: PMC23130] [PubMed: 9256465]
- de WinterJP, Waisfisz Q, Rooimans MA. et al. The Fanconi anaemia group G gene FANCG is identical with XRCC9. Nat Genet. 1998;20(3):281–283. [PubMed: 9806548]
- Kuang Y, Garcia-Higuera I, Moran A. et al. Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity. Blood. 2000;96(5):1625–1632. [PubMed: 10961856]
- Futaki M, Watanabe S, Kajigaya S. et al. Fanconi anemia protein, FANCG, is a phosphoprotein and is upregulated with FANCA after TNF-alpha treatment. Biochem Biophys Res Commun. 2001;281(2):347–351. [PubMed: 11181053]
- Mi J, Qiao F, Wilson JB. et al. FANCG is phosphorylated at serines 383 and 387 during mitosis. Mol Cell Biol. 2004;24(19):8576–8585. [PMC free article: PMC516759] [PubMed: 15367677]
- Qiao FY, Mi J, Wilson JB. et al. Phosphorylation of Fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway. Journal of Biological Chemistry. 2004;279(44):46035–46045. [PubMed: 15299017]
- Demuth I, Wlodarski M, Tipping AJ. et al. Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9. Eur J Hum Genet. 2000;8(11):861–868. [PubMed: 11093276]
- Auerbach AD, Greenbaum J, Pujara K. et al. Spectrum of sequence variation in the FANCG gene: An International Fanconi Anemia Registry (IFAR) study. Hum Mutat. 2003;21(2):158–168. [PubMed: 12552564]
- Morgan NV, Essop F, Demuth I. et al. A common Fanconi Anemia mutation in black populations of sub-Saharan Africa. Blood. 2005 [PubMed: 15657175]
- Liu FH, Wu SJ, Hu SM. et al. Specific interaction of the 70-kDa heat shock cognate protein with the tetratricopeptide repeats. J Biol Chem. 1999;274(48):34425–34432. [PubMed: 10567422]
- Russell LC, Whitt SR, Chen MS. et al. Identification of conserved residues required for the binding of a tetratricopeptide repeat domain to heat shock protein 90. J Biol Chem. 1999;274(29):20060–20063. [PubMed: 10400612]
- Scheufler C, Brinker A, Bourenkov G. et al. Structure of TPR domain-peptide complexes: Critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell. 2000;101(2):199–210. [PubMed: 10786835]
- Joenje H, Levitus M, Waisfisz Q. et al. Complementation analysis in fanconi anemia: Assignment of the reference FA-H Patient to Group A. Am J Hum Genet. 2000;67(3):759–762. [PMC free article: PMC1287536] [PubMed: 10936108]
- Meetei AR, Yan Z, Wang W. FANCL Replaces BRCA1 as the likely ubiquitin ligase responsible for FANCD2 monoubiquitination. Cell Cycle. 2004;3(2):179–181. [PubMed: 14712086]
- de Winter JP, van Der WL, De Groot J. et al. The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum Mol Genet. 2000;9(18):2665–2674. [PubMed: 11063725]
- Garcia-Higuera I, Kuang Y, Denham J. et al. The Fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex. Blood. 2000;96(9):3224–3230. [PubMed: 11050007]
- Medhurst AL, Huber PA, Waisfisz Q. et al. Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway. Hum Mol Genet. 2001;10(4):423–429. [PubMed: 11157805]
- Waisfisz Q, de WinterJP, Kruyt FA. et al. A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. Proc Natl Acad Sci USA. 1999;96(18):10320–10325. [PMC free article: PMC17886] [PubMed: 10468606]
- Kupfer GM, Näf D, Suliman A. et al. The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. Nature Genet. 1997;17:487–490. [PubMed: 9398857]
- Hirano S, Yamamoto K, Ishiai M. et al. Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM. EMBO J. 2005;24(2):418–427. [PMC free article: PMC545820] [PubMed: 15616572]
- Rothfuss A, Grompe M. Repair kinetics of genomic interstrand DNA cross-links: Evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway. Mol Cell Biol. 2004;24(1):123–134. [PMC free article: PMC303365] [PubMed: 14673148]
- Xia F, Taghian DG, DeFrank JS. et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc Natl Acad Sci USA. 2001;98(15):8644–8649. [PMC free article: PMC37489] [PubMed: 11447276]
- Gowen LC, Avrutskaya AV, Latour AM. et al. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science. 1998;281(5379):1009–1012. [PubMed: 9703501]
- Husain A, He GS, Venkatraman ES. et al. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II) Cancer Res. 1998;58(6):1120–1123. [PubMed: 9515792]
- Le PageF, Randrianarison V, Marot D. et al. BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res. 2000;60(19):5548–5552. [PubMed: 11034101]
- Aprelikova O, Pace AJ, Fang B. et al. BRCA1 is a selective coactivator of 14-3-3 sigma gene transcription in mouse embryonic stem cells. J Biol Chem. 2001;276(28):25647–25650. [PubMed: 11384963]
- Yarden RI, Brody LC. BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci USA. 1999;96(9):4983–4988. [PMC free article: PMC21803] [PubMed: 10220405]
- Zhang HB, Somasundaram K, Peng Y. et al. BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene. 1998;16(13):1713–1721. [PubMed: 9582019]
- Zheng L, Li S, Boyer TG. et al. Lessons learned from BRCA1 and BRCA2. Oncogene. 2000;19(53):6159–6175. [PubMed: 11156530]
- Siddique H, Zou JP, Rao VN. et al. The BRCA2 is a histone acetyltransferase. Oncogene. 1998;16(17):2283–2285. [PubMed: 9619837]
- Gao B, Shen XN, Kunos G. et al. Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. FEBS Lett. 2001;488(3):179–184. [PubMed: 11163768]
- Kubista M, Rosner M, Kubista E. et al. Brca1 regulates in vitro differentiation of mammary epithelial cells. Oncogene. 2002;21(31):4747–4756. [PubMed: 12101413]
- Meetei AR, Sechi S, Wallisch M. et al. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol. 2003;23(10):3417–3426. [PMC free article: PMC164758] [PubMed: 12724401]
- Garcia-Higuera I, Kuang Y, D'Andrea AD. The molecular and cellular biology of Fanconi anemia. Curr Opin Hematol. 1999;6(2):83–88. [PubMed: 10088637]
- Kruyt FA, Hoshino T, Liu JM. et al. Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase. Blood. 1998;92(9):3050–3056. [PubMed: 9787138]
- Dai MS, Chevallier N, Stone S. et al. The effects of the Fanconi anemia zinc finger (FAZF) on cell cycle, apoptosis, and proliferation are differentiation stage-specific. Journal of Biological Chemistry. 2002;277(29):26327–26334. [PubMed: 11986317]
- Hoatlin ME, Zhi Y, Ball H. et al. A novel BTB/POZ transcriptional repressor protein interacts with the fanconi anemia group C protein and PLZF. Blood. 1999;94(11):3737–3747. [PubMed: 10572087]
- Hoshino T, Wang JX, Devetten MP. et al. Molecular chaperone GRP94 binds to the Fanconi anemia group C protein and regulates its intracellular expression. Blood. 1998;91(11):4379–4386. [PubMed: 9596688]
- Kruyt FA, Dijkmans LM, Arwert F. et al. Involvement of the Fanconi's anemia protein FAC in a pathway that signals to the cyclin B/cdc2 kinase. Cancer Res. 1997;57(11):2244–2251. [PubMed: 9187128]
- Sridharan D, Brown M, Lambert WC. et al. Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links. J Cell Sci. 2003;116(Pt 5):823–835. [PubMed: 12571280]
- Otsuki T, Kajigaya S, Ozawa K. et al. SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein. Biochem Biophys Res Commun. 1999;265(3):630–635. [PubMed: 10600472]
- Futaki M, Igarashi T, Watanabe S. et al. The FANCG Fanconi anemia protein interacts with CYP2E1: Possible role in protection against oxidative DNA damage. Carcinogenesis. 2002;23(1):67–72. [PubMed: 11756225]
Grover C Bagby, Jr.*.
Landes Bioscience, Austin (TX)
Bagby, Jr. GC. The Genetic Basis of Fanconi Anemia. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.