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

Jana Peremartí1, Facundo Ramos1, Ricard Marcos2

  • 1Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|August 6, 2014
PubMed

Insights

Chronic arsenic exposure disrupts the Fanconi anemia (FA)/BRCA pathway, a critical DNA repair mechanism. This interference leads to increased genomic instability and cancer risk, highlighting a novel mechanism for arsenic

Area of Science:

  • Environmental Health
  • Molecular Biology
  • Genetics

Background:

  • Chronic arsenic exposure is a known genotoxic agent, impairing DNA repair pathways like nucleotide excision repair and base excision repair.
  • The Fanconi anemia (FA)/BRCA pathway is crucial for maintaining genomic stability and preventing cancer by repairing DNA damage.
  • Interactions between arsenic and the FA/BRCA pathway are not well understood, representing a gap in knowledge regarding arsenic's carcinogenic mechanisms.

Purpose of the Study:

  • To investigate the effects of trivalent arsenic compounds on the FA/BRCA DNA repair pathway.
  • To determine if arsenic exposure disrupts the normal function of the FA/BRCA pathway in human cells.
  • To explore a novel mechanism contributing to arsenic's co-carcinogenic effects.

Main Methods:

  • Utilized isogenic human fibroblast cell lines: FANCD2(-/-) (FA/BRCA-deficient) and FANCD2(+/+) (FA/BRCA-corrected).
  • Preexposed corrected FANCD2(+/+) cells to subtoxic concentrations of methylarsonous acid (MMA(III)) and arsenic trioxide (ATO) for two weeks.
  • Evaluated cellular responses to DNA-damaging agents (mitomycin-C, hydroxyurea, diepoxybutane) in preexposed cells and compared them to FA/BRCA-deficient cells.

Main Results:

  • Arsenic preexposure in corrected cells induced a FA/BRCA-deficient phenotype.
  • Cells preexposed to MMA(III) and ATO exhibited hypersensitivity to DNA-damaging agents.
  • Enhanced G2/M cell cycle arrest and increased genomic instability (micronuclei formation) were observed in arsenic-exposed cells.

Conclusions:

  • Environmentally relevant arsenic exposures disrupt the normal function of the FA/BRCA DNA repair pathway.
  • Arsenic-induced FA/BRCA dysfunction contributes to genomic instability and enhances co-carcinogenic effects.
  • This study establishes the first link between arsenic exposure and the FA/BRCA DNA repair pathway, revealing a novel mechanism of arsenic toxicity.
Keywords:
DNA repairFANCD2-deficientFanconi anemia FA/BRCA pathwaygenomic instabilityinterstrand crosslinkstrivalent arsenic compounds

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