title: Activation of the Fanconi anemia/BRCA pathway at low doses of ionization radiation.
abstract: Fanconi anemia (FA) is a rare, clinically heterogeneous autosomal recessive or X-linked genetic disease characterized by chromosome fragility, congenital malformations and cancer susceptibility. FA patients are usually radiosensitive when exposed to radiotherapy but the role of the FA in response to ionizing radiation (IR) is controversial. Here we have investigated IR-induced activation of the FA pathway by systematically analyzing monoubiquitination of the central protein FANCD2 and subsequent recruitment to stalled replication forks in primary fibroblasts. We developed an immunolabelling method to simultaneously visualize IR-induced FANCD2 and γH2AX foci in S-phase. We observed FANCD2 foci formation in a subset of IR-induced γH2AX foci in S-phase cells. This was observed at doses of IR ranging from 0.1 to 5.0Gy in a dose dependent non-threshold fashion. Our results indicate that minimum doses of IR can produce replication fork stalling and FA pathway activation during S-phase in primary cells.
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Pau Castillo
authors.initials: PC
authors.lastname: Bosch
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bogliolo
authors.affiliation: Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain and Centre for Biomedical Network Research on Rare Diseases (CIBERER), Spain. Electronic address: jordi.surralles@uab.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
mesh_terms: D002460:Cell Line; D002675:Child, Preschool; D004307:Dose-Response Relationship, Radiation; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011839:Radiation, Ionizing; D016196:S Phase / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects*; D054875:Ubiquitination
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C468783:H2AX protein, human; D006657:Histones
keywords: DNA damage response; FANCD2; Fanconi anemia; Ionizing radiation; γH2AX