Comment on Taniguchi and D'Andrea, page 4223

Fanconi anemia is a genetic instability syndrome characterized by bone marrow failure and high relative risks of myelodysplasia and acute myelogenous leukemia. Eleven of the genes and gene products have been identified, and their role in protecting the genome is being intensively investigated. The roles of these proteins in hematopoietic regulation are less broadly studied but likely involve separate biochemical functions.

The review of Fanconi anemia (FA) in this issue by Taniguchi and D'Andrea is an outstanding summary of the state of FA research from the laboratory of an investigator who has contributed enormously to the field. The authors chose to focus their review entirely on DNA damage recognition/repair. In fact, that is where the action has been. Only about 5% of the published literature on FA has had to do directly with hematologic disease. Since blood is what this journal is about, we ought to pay attention to information in this paper that might contain some clues about the noncanonical functions of these proteins, some of which might have to do with molecular pathogenesis in the hematopoietic system.

FA cells are hypersensitive to cross-linking agents, an abnormality upon which the diagnostic tests are based; yet although all somatic cells are hypersensitive to these agents, no other organ system fails as consistently as the bone marrow. Moreover, bone marrow failure represents an enormous threat to the well-being and survival of FA patients. Consequently, while the FA proteins play a key role by working together to protect the genome from damage induced by cross-linking agents, it also seems likely that they play other unique roles in hematopoietic cells. There is abundant evidence in support of this idea.

For example, the canonical nuclear FA complex so nicely described in this review is not the only multimeric complex formed by these proteins. There are complexes galore, both nuclear and cytoplasmic,1-3  and these complexes, often containing well-known signaling proteins2,4  and chaperones,5  can form dynamically in response to environmental stressors broader in scope than bifunctional alkylating agents (see figure). Could the DNA damage-related function of these proteins underlie all of these effects? Theoretically, DNA damage in the ground state might lower the apoptotic threshold in all cells. However, experimental evidence using laboratory-generated mutant forms of FANCC cDNA indicates that one can correct the abnormal DNA damage response of FA cells without fixing their apoptosis-inducing cytokine hypersensitivity responses,6  formally demonstrating molecular multifunctionality at least for FANCC. There is more evidence to come in support of multifunctionality of other FA proteins.FIG1 

FA proteins (shown as lettered ovals) exist in various multimeric complexes in the cytoplasm and nucleus. The nuclear core complex facilitates the monoubiquitination (Ub) of FANCD2 (D2) protecting cells from genetic damage and death following exposure to cross-linking agents. Cytoplasmic complexes are also found, and there is emerging evidence that various FA complexes, often acting in concert with heat shock proteins, function to suppress the activation state of intracellular effectors of apoptosis (promoting survival) and facilitate survival signaling pathways including those that involve JAK-dependent STAT activation (promoting survival). Thus, FA cells are intolerant of a variety of extracellular stresses, not just cross-linking agents. The nuclear core complex shown is known to exist. The exact composition of the cytoplasmic FA complexes has not been fully defined, so in this figure the complex shown is meant to be generically reflective of multiple subcomplexes that are known to exist and of subcomplexes that will be identified in the future. Illustration by Marie Dauenheimer.

FA proteins (shown as lettered ovals) exist in various multimeric complexes in the cytoplasm and nucleus. The nuclear core complex facilitates the monoubiquitination (Ub) of FANCD2 (D2) protecting cells from genetic damage and death following exposure to cross-linking agents. Cytoplasmic complexes are also found, and there is emerging evidence that various FA complexes, often acting in concert with heat shock proteins, function to suppress the activation state of intracellular effectors of apoptosis (promoting survival) and facilitate survival signaling pathways including those that involve JAK-dependent STAT activation (promoting survival). Thus, FA cells are intolerant of a variety of extracellular stresses, not just cross-linking agents. The nuclear core complex shown is known to exist. The exact composition of the cytoplasmic FA complexes has not been fully defined, so in this figure the complex shown is meant to be generically reflective of multiple subcomplexes that are known to exist and of subcomplexes that will be identified in the future. Illustration by Marie Dauenheimer.

The work reviewed by Taniguchi and D'Andrea is helpful because genetic instability is an element that plays a key role in the evolution of neoplastic clones and must be understood. The study also provides a starting point that informs hematology researchers that the proteins form multimeric complexes and influence posttranslational modifications of other proteins. But noncanonical functions represent the road less traveled by, and these are the ones that hold promise for the hematology research community. We will not understand the anemia part of FA, or the myelodysplasia and leukemia for that matter, by subscribing to a view of the nuclear DNA damage pathway as the pathway. At the end of the day, the “linear” nuclear pathway will be only one element of a complex network of multifunctional proteins that evolved beautifully, perhaps as scaffolds or cochaperones, to organize multiple protective responses against multiple environmental stresses. ▪

1
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2
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Pang QS, Christianson TA, Keeble W, Koretsky T, Bagby GC. 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.
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