Arsenic exposure disrupts the normal function of the FA/BRCA repair pathway

Jana Peremartí, Facundo Ramos, Ricard Marcos, Alba Hernández

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

© The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. 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 (MMAIII) 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 MMAIII 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.
Original languageEnglish
Pages (from-to)93-104
JournalToxicological Sciences
Volume142
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • DNA repair
  • FANCD2-deficient
  • Fanconi anemia FA/BRCA pathway
  • Genomic instability
  • Interstrand crosslinks
  • Trivalent arsenic compounds

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