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Arsenic affects homologous recombination and single-strand annealing but not end-joining pathways during DNA

Aya Kurosawa1,2,3, Shinta Saito1, Mikiko Sakurai1

  • 1Graduate School of Nanobioscience, Yokohama City University, Japan.

The FEBS Journal
|August 2, 2023
PubMed

Insights

Arsenic trioxide suppresses homologous recombination (HR), a key DNA repair pathway. This suppression contributes to genomic instability and may explain arsenic-induced cancer and enhanced sensitivity to certain cancer drugs.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Arsenic is a known carcinogen linked to various cancers.
  • DNA double-strand breaks (DSBs) are implicated in arsenic-induced carcinogenesis, but the precise mechanisms are not fully understood.
  • Understanding how arsenic affects DNA repair is crucial for elucidating its carcinogenic potential.

Purpose of the Study:

  • To investigate the impact of arsenic trioxide (As2O3) on different DNA double-strand break (DSB) repair pathways.
  • To determine the role of DSB repair pathway modulation in arsenic-induced genomic instability and carcinogenesis.
  • To explore potential therapeutic implications of arsenic's effects on DNA repair.

Main Methods:

  • Genetic analysis of four DSB repair pathways in the human pre-B cell line Nalm-6.
  • Assessment of non-homologous end joining (NHEJ), polymerase theta-mediated end joining (Poliθ-MMEJ), homologous recombination (HR), and single-strand annealing (SSA) efficiencies.
  • Evaluation of cellular sensitivity to olaparib and camptothecin in the presence of As2O3.

Main Results:

  • Arsenic trioxide (As2O3) did not significantly impair NHEJ or Poliθ-MMEJ.
  • As2O3 demonstrably decreased the efficiency of homologous recombination (HR) and, to a lesser extent, single-strand annealing (SSA).
  • As2O3 treatment enhanced sensitivity to olaparib and camptothecin in HR-proficient cells, indicating compromised HR repair.

Conclusions:

  • Arsenic trioxide suppresses homologous recombination (HR), a critical DNA repair pathway.
  • The inhibition of HR by arsenic contributes to genomic instability, offering a mechanistic insight into arsenic-induced carcinogenesis.
  • These findings suggest potential therapeutic strategies by targeting HR in arsenic-exposed individuals or cancers.
Keywords:
arsenichomologous recombinationnon-homologous end joiningpolymerase theta-mediated end joiningsingle-strand annealing

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