title: Arsenic exposure disrupts the normal function of the FA/BRCA repair pathway.
abstract: Chronic arsenic exposure is known to enhance the genotoxicity/carcinogenicity of other DNA-damaging agents by inhibiting DNA repair activities. Interference with nucleotide excision repair and base excision repair are well documented, but interactions with other DNA repair pathways are poorly explored so far. The Fanconi anemia FA/BRCA pathway is a DNA repair mechanism required for maintaining genomic stability and preventing cancer. Here, interactions between arsenic compounds and the FA/BRCA pathway were explored by using isogenic FANCD2(-/-) (FA/BRCA-deficient) and FANCD2(+/+) (FA/BRCA-corrected) human fibroblasts. To study whether arsenic disrupts the normal FA/BRCA function, FANCD2(+/+) cells were preexposed to subtoxic concentrations of the trivalent arsenic compounds methylarsonous acid (MMA(III)) and arsenic trioxide (ATO) for 2 weeks. The cellular response to mitomicin-C, hydroxyurea, or diepoxybutane, typical inducers of the studied pathway, was then evaluated and compared to that of FANCD2(-/-) cells. Our results show that preexposure to the trivalent arsenicals MMA(III) and ATO induces in corrected cells, a cellular FA/BRCA-deficient phenotype characterized by hypersensitivity, enhanced accumulation in the G2/M compartment and increased genomic instability--measured as micronuclei. Overall, our data demonstrate that environmentally relevant arsenic exposures disrupt the normal function of the FA/BRCA activity, supporting a novel source of arsenic co- and carcinogenic effects. This is the first study linking arsenic exposure with the FA/BRCA DNA repair pathway.
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Jana
authors.initials: J
authors.lastname: Peremartí
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Facundo
authors.initials: F
authors.lastname: Ramos
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain CIBER Epidemiología y Salud Pública, ISCIII, 28029 Madrid, Spain alba.hernandez@uab.es.
authors.forename: Ricard
authors.initials: R
authors.lastname: Marcos
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain CIBER Epidemiología y Salud Pública, ISCIII, 28029 Madrid, Spain alba.hernandez@uab.es.
authors.forename: Alba
authors.initials: A
authors.lastname: Hernández
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D015162:Micronucleus Tests; D010087:Oxides / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D023382:Toxicity Tests, Acute
chemical_list: D001152:Arsenicals; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D010087:Oxides; C020300:monomethylarsonic acid; D000077237:Arsenic Trioxide
keywords: DNA repair; FANCD2-deficient; Fanconi anemia FA/BRCA pathway; genomic instability; interstrand crosslinks; trivalent arsenic compounds