Cited by 39DNA Repair MechanismsArsenic contamination and mitigationCarcinogens and Genotoxicity Assessment

Oxidative Stress and Replication-Independent DNA Breakage Induced by Arsenic in Saccharomyces cerevisiae

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Litwin, Ireneusz, Bocer, Tomasz, Dziadkowiec, Dorota, Wysocki, Robert·2013·PLoS Genetics

Abstract

Arsenic is a well-established human carcinogen of poorly understood mechanism of genotoxicity. It is generally accepted that arsenic acts indirectly by generating oxidative DNA damage that can be converted to replication-dependent DNA double-strand breaks (DSBs), as well as by interfering with DNA repair pathways and DNA methylation. Here we show that in budding yeast arsenic also causes replication and transcription-independent DSBs in all phases of the cell cycle, suggesting a direct genotoxic mode of arsenic action. This is accompanied by DNA damage checkpoint activation resulting in cell cycle delays in S and G2/M phases in wild type cells. In G1 phase, arsenic activates DNA damage response only in the absence of the Yku70-Yku80 complex which normally binds to DNA ends and inhibits resection of DSBs. This strongly indicates that DSBs are produced by arsenic in G1 but DNA ends are protected by Yku70-Yku80 and thus invisible for the checkpoint response. Arsenic-induced DSBs are processed by homologous recombination (HR), as shown by Rfa1 and Rad52 nuclear foci formation and requirement of HR proteins for cell survival during arsenic exposure. We show further that arsenic greatly sensitizes yeast to phleomycin as simultaneous treatment results in profound accumulation of DSBs. Importantly, we observed a similar response in fission yeast Schizosaccharomyces pombe, suggesting that the mechanisms of As(III) genotoxicity may be conserved in other organisms.

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  1. [58]Nikolova T, Ensminger M, Löbrich M, Kaina B (2010) Homologous recombination protects mammalian cells from replication-associated DNA double-strand breaks arising in response to methyl methanesulfonate. DNA Repair (Amst) 9: 1050– 1063. 20708982

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Authors
Litwin, I., Bocer, T., Dziadkowiec, D., & Wysocki, R.
Affiliations
  • University of Wrocław (PL)
  • University of Rzeszów (PL)
Corresponding author
Wysocki, Robert
Venue
PLoS Genetics
Published
2013-07-25
Volume
9
Issue
7
Pages
e1003640
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
OpenAlex
W2073271772
Cited by
39
References
70
Citations by year
2025: 2 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 8 · 2017: 4 · 2016: 2 · 2014: 3 · 2013: 1
FWCI
0.90
Type
journal article
Language
en
Open access
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Physical Sciences › Environmental Science › Environmental Chemistry › Arsenic contamination and mitigation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords
arsenic, arsenite, genotoxicity, oxidative DNA damage, DNA damage checkpoint, DNA end protection, homologous recombination, RAD52, Rfa1, Saccharomyces cerevisiae, Schizosaccharomyces pombe, cell cycle arrest
MeSH terms
Arsenic, DNA Repair, DNA Replication, DNA-Binding Proteins, Humans, Saccharomyces cerevisiae, Schizosaccharomyces, Oxidative Stress, Evolution, Molecular, DNA Methylation, Saccharomyces cerevisiae Proteins, Replication Protein A, Rad52 DNA Repair and Recombination Protein, DNA Breaks, Double-Stranded, Cell Cycle Checkpoints, Homologous Recombination

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