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Cited by 63Cancer therapeutics and mechanismsDNA Repair MechanismsBioactive Compounds and Antitumor Agents

Type II topoisomerases--inhibitors, repair mechanisms and mutations

Heisig, P.·2009·Mutagenesis
DOI 10.1093/mutage/gep035
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Abstract

Type II topoisomerases are ubiquitous enzymes that play an essential role in the control of replicative DNA synthesis and share structural and functional homology among different prokaryotic and eukaryotic organisms. Antibacterial fluoroquinolones target prokaryotic topoisomerases at concentrations 100- to 1000-fold lower than mammalian enzymes, the preferred targets of anticancer drugs such as etoposide. The mechanisms of action of both of these types of inhibitors involve the fixation of an intermediate reaction step, where the enzyme is covalently bound to an enzyme-mediated DNA double-strand break (DSB). The resulting ternary drug-enzyme-DNA complexes can then be converted to cleavage complexes that block further movement of the DNA replication fork, subsequently inducing stress responses. In haploid prokaryotic cells, stress responses include error-free and error-prone DNA damage repair pathways, such as homologous recombination and translesion synthesis, respectively. The latter can result in the acquisition of point mutations. Diploid mammalian cells are assumed to preferentially use recombination mechanisms for the repair of DSBs, an example of which, non-homologous end joining, is a major error-prone repair mechanism associated with an increased frequency of detectable small deletions, insertions and translocations. However, results obtained from safety testing of novel fluoroquinolones at high concentrations indicate that point mutations may also occur in mammalian cells. Recent data provide evidence for translesion synthesis catalysed by error-prone repair polymerases as a damage-tolerance repair mechanism of DSBs in eukaryotic cells. This paper discusses possible roles of different mechanisms for the repair of DSBs operating in both eukaryotic and prokaryotic cells that result in recombinational rearrangements, deletions/insertions as well as point mutations.

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Authors
Heisig, P.
Affiliations
Universität Hamburg (DE)
Corresponding author
Heisig, P.
ORCID
Heisig, P.
Venue
Mutagenesis
Publisher
Oxford University Press (OUP)
Published
2009-09-17
Volume
24
Issue
6
Pages
465-469
ISSN
  • 0267-8357 (ISSN-L)
  • 1464-3804
DOI
10.1093/mutage/gep035
OpenAlex
W2159174329
Cited by
63
References
74
Citations by year
2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 5 · 2013: 8 · 2012: 9
FWCI
0.59
Type
journal article
Language
en
Open access
closed
Locations
  • Mutagenesis (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords
topoisomerase II, topoisomerase inhibitors, fluoroquinolones, etoposide, DNA double-strand break repair, translesion synthesis, homologous recombination, non-homologous end joining, point mutations, error-prone DNA repair, DNA damage tolerance
MeSH terms
Animals, Bacteria, DNA Damage, DNA Topoisomerases, Type II, DNA Repair, DNA Replication, Enzyme Inhibitors, Humans, Mutation, Recombination, Genetic, Point Mutation, Fluoroquinolones, DNA Breaks, Double-Stranded, Topoisomerase II Inhibitors

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