title: The clastogenic response of the 1q12 heterochromatic region to DNA cross-linking agents is independent of the Fanconi anaemia pathway.
abstract: 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.
authors.affiliation: Group of Mutagenesis, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Callén
authors.forename: M J
authors.initials: MJ
authors.lastname: Ramírez
authors.forename: A
authors.initials: A
authors.lastname: Creus
authors.forename: R
authors.initials: R
authors.lastname: Marcos
authors.forename: S
authors.initials: S
authors.lastname: Frias
authors.forename: B
authors.initials: B
authors.lastname: Molina
authors.forename: I
authors.initials: I
authors.lastname: Badell
authors.forename: T
authors.initials: T
authors.lastname: Olivé
authors.forename: J J
authors.initials: JJ
authors.lastname: Ortega
authors.forename: J
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D003432:Cross-Linking Reagents / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity*; D005199:Fanconi Anemia / Q000235:genetics*; D006580:Genetic Carrier Screening; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D016685:Mitomycin / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*
chemical_list: D003432:Cross-Linking Reagents; D004852:Epoxy Compounds; D009153:Mutagens; D016685:Mitomycin; C007366:diepoxybutane