Fanconi anaemia (FA) is a rare genetic syndrome of
cancer susceptibility characterized by spontaneous and induced
chromosome fragility, especially
after treatment with cross-linking agents. Recent investigations showed interactions between FA
proteins and
chromatin remodelling factors. To investigate a potential uneven distribution of the FA pathway through the human genome depending on
chromatin conformation, we have analysed
chromosome breakage in the largest constitutively heterochromatic region in the human genome, the 1q12 band, in lymphocytes from FA patients, carriers and healthy controls
after treatment with the cross-linking agents
mitomycin-C (MMC) and
diepoxybutane (DEB). As expected, a higher level of MMC-induced cytotoxicity and
chromosome breakage was observed in cells from FA patients when compared with normal controls and carriers. However, the increase in 1q12 breakage after increasing concentrations of MMC was of a similar magnitude in FA patients, carriers and controls. Similarly, DEB induced a high level of overall genome
chromosome fragility in cells from FA patients when compared with controls with no parallel increase in
chromosome breaks specifically involving the heterochromatic band 1q12. We therefore conclude that, unlike the overall genome, the sensitivity of chromosome 1 constitutive
heterochromatin to the chromosome breaking activity of cross-linking agents is independent of a functional FA pathway, indicating that the action of the FA pathway is unevenly distributed through the human genome.