Oxidative stress as a multiple effector in Fanconi anaemia clinical phenotype.
Fanconi anaemia (FA) is a genetic disease characterised by bone marrow failure with excess risk of myelogenous leukaemia and solid tumours. A widely accepted notion in FA research invokes a deficiency of response to DNA damage as the fundamental basis of the 'crosslinker sensitivity' observed in this disorder. However, such an isolated defect cannot readily account for the full cellular and clinical phenotype, which includes a number of other abnormalities, such as malformations, endocrinopathies, and typical skin spots. An extensive body of evidence pointing toward an involvement of oxidative stress in the FA phenotype includes the following: (i) In vitro and ex vivo abnormalities in a number of redox status endpoints; (ii) the functions of several FA proteins in protecting cells from oxidative stress; (iii) redox-related toxicity mechanisms of the xenobiotics evoking excess toxicity in FA cells. The clinical features in FA and the in vivo abnormalities of redox parameters are here reconsidered in view of the pleiotropic clinical phenotype and known biochemical and molecular links to an in vivo prooxidant state, which causes oxidative damage to biomolecules, resulting in an excessive number of acquired abnormalities that may overwhelm the cellular repair capacity rather than a primary deficiency in DNA repair. FA may thus represent a unique model disease in testing the integration between the acquisition of macromolecular damage as a result of oxidative stress and the ability of the mammalian cell to respond effectively to such damage.
Pagano
Giovanni
G
Centre for Research, Innovation and Technological Transfer in Oncology and Life Sciences, Mercogliano (AV), Italy. gbpagano@tin.it
Degan
Paolo
P
d'Ischia
Marco
M
Kelly
Frank J
FJ
Nobili
Bruno
B
Pallardó
Federico V
FV
Youssoufian
Hagop
H
Zatterale
Adriana
A
D018797:Cell Cycle Proteins / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D005199:Fanconi Anemia / Q000378:metabolism* / Q000473:pathology*; D051856:Fanconi Anemia Complementation Group Proteins; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins