Reply
The letter by Drs Pagano and Rutherford criticizes our recent review 'The Fanconi anaemia/BRCA pathway' (Nature Rev Cancer 3, 23–34) for failing to give due coverage to those reports connecting Fanconi anaemia (FA) to oxidative damage and oxygen metabolism. We are aware of the papers cited here to support the oxidative stress hypothesis for FA, but chose to focus on those parts of the FA literature that have stood the test of time and are likely to contribute to the final understanding of this important disease. This reflects our personal bias that the published work on oxidative damage and FA describes only secondary phenotypes (epiphenomena) rather than the primary defect in FA.
The statement by Drs Pagano and Rutherford that the 'crosslinker sensitivity' of FA cells is due to the formation of reactive oxygen species is incorrect. FA cells are exquisitely sensitive to photoactivated psoralen1,2. Crosslink formation by this regimen is a reaction that does not require any biotransformation or oxygen whatsoever and can be done on naked DNA3. Whereas primary FA cells display moderate sensitivity to molecular oxygen, this phenotype is not preserved in immortal FA cells, even though they remain crosslinker sensitive4. The lack of sensitivity of FA cells to H2O2 has been shown by several labs4,5.
Several FA proteins have been reported to interact with various cytoplasmic proteins that are involved in oxygen metabolism (such as NADPH cytochrome P450 reductase6, CYP2E1 (Ref. 7) and GSTP1 (Ref. 8)), but these interactions have not been shown to be functionally important by genetic approaches. In addition to interactions with oxidative-stress-related proteins, there are many other reported protein–protein interactions of FA proteins9,10,11,12. All of these are of unknown physiological significance and have generated a plethora of hypotheses regarding the functions of FA proteins. We limited our review to cover functions that could be corroborated by several lines of evidence.
Finally, we wish to make it clear that we do believe oxygen to be one of the many genotoxic agents to which FA cells are modestly sensitive. For example, mice with disruptions in genes encoding both superoxide dismutase and Fancc have some additive phenotypes13. Furthermore, our own results indicate that H2O2 can induce the mono-ubiquitylation of FANCD2, in a similar way to ionizing radiation, ultraviolet-C light and many other DNA-damaging agents. Clearly, oxygen produces some DNA lesions that can be processed through the FA pathway. However, there is no direct evidence to support a role for any FA proteins in oxygen responses that are independent of DNA repair (i.e. cytoplasmic pre-repair functions, such as oxygen radical detoxification).
Our review does not claim that FA proteins function only in crosslink repair. On the other hand, many reports show that crosslinker sensitivity is a hallmark for defects in homologous recombination repair14.
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Grompe, M., D'Andrea, A. Reply to “Involvement of oxidative stress in Fanconi's anaemia: from phenotype to FA protein functions”. Nat Rev Cancer 3, 78 (2003). https://doi.org/10.1038/nrc970-c2
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DOI: https://doi.org/10.1038/nrc970-c2
