Sirs
The article 'The Fanconi anaemia/BRCA pathway' by Alan D. D'Andrea and Markus Grompe published in the January issue (Nature Rev. Cancer 3, 23–33) provided a formidable synopsis of the studies conducted by the authors and by other scientists in relating Fanconi anaemia (FA) proteins with a DNA-repair deficiency in FA. This review, however, fails to mention a body of pertinent literature that is outside the authors' theory that DNA damage is the primary event, then followed by FA-protein-associated DNA repair.
First, the widespread definition of FA phenotype as related to 'crosslinker sensitivity' is focused on the end products of some xenobiotics (such as mitomycin C, diepoxybutane and cisplatin). This assumption conflicts with the established evidence, dating back to almost 40 years, that the above chemicals exert their toxicities via mechanisms of action requiring their biotransformation to reactive metabolites, are associated with the formation of reactive oxygen species1,2,3,4,5 and depend on oxygen levels6,7.
When reporting on FA's phenotypic features (Box 1 in their article), D'Andrea and Grompe cite from their own review paper that they published in 1997 (Ref. 8). Regarding the issue termed as 'sensitivity to oxygen', the authors cited from a set of literature that was outdated even at that time, the most recent paper dating back to 1993. So, the whole subject of FA-associated pro-oxidant state should be supposed to be unchanged in the past 10 years. This is evidently not the case, as reviewed recently by Pagano and Youssoufian9.
Last, but not least, the authors fail to mention a set of information that relates the functions of FA-C and FA-G with redox-related pathways10,11,12. These two members of the FA protein complex have been shown to be involved in redox-modulated activation (FA-C and FA-G)10,12 and in detoxification of xenobiotics (FA-C)11. The direct involvement of FA-C and FA-G in redox homeostasis is not the only matter of concern pointing to the multiple roles of FA proteins in xenobiotic detoxification and in counteracting oxidative stress. A number of other indirect links can be traced, such as the roles for BRCA1, BRCA2 and ATM in the specific repair of oxidative DNA damage (BRCA) and as a sensor of oxidative stress (ATM) (reviewed in Ref. 9).
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Pagano, G., Rutherford, T. 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-c1
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DOI: https://doi.org/10.1038/nrc970-c1
