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Related Concept Videos

Overview of DNA Repair02:25

Overview of DNA Repair

In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
Overview of DNA Repair02:25

Overview of DNA Repair

In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...
Nucleotide Excision Repair01:38

Nucleotide Excision Repair

DNA Distortion and Damage
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
Nucleotide Excision Repair01:08

Nucleotide Excision Repair

Overview
Nucleotide Excision Repair01:08

Nucleotide Excision Repair

Overview
Spontaneous and Induced Mutations01:30

Spontaneous and Induced Mutations

Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).

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Quantification of three DNA Lesions by Mass Spectrometry and Assessment of Their Levels in Tissues of Mice Exposed to Ambient Fine Particulate Matter
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5-Lipoxygenase-mediated endogenous DNA damage.

Wenying Jian1, Seon Hwa Lee1, Michelle V Williams1

  • 1From the Centers for Cancer Pharmacology and Excellence in Environmental Toxicology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160.

The Journal of Biological Chemistry
|April 25, 2009
PubMed
Summary

The 5-lipoxygenase (5-LO) enzyme generates lipid hydroperoxides that lead to DNA damage. This study confirms 5-LO is responsible for forming mutagenic 4-oxo-2(E)-nonenal-derived DNA adducts in human cells.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Lipoxygenases (LOs) metabolize polyunsaturated fatty acids into lipid hydroperoxides.
  • The homolytic decomposition of lipid hydroperoxides generates genotoxins, such as 4-oxo-2(E)-nonenal, which form mutagenic DNA adducts.
  • Understanding the specific enzymes involved in DNA adduct formation is crucial for assessing genotoxic risk.

Purpose of the Study:

  • To identify the specific lipoxygenase enzyme responsible for endogenous DNA adduct formation.
  • To investigate the role of 5-lipoxygenase (5-LO) in generating 4-oxo-2(E)-nonenal-derived DNA adducts.
  • To analyze the impact of FLAP inhibition on DNA adduct levels.

Main Methods:

  • Chiral lipidomics analysis of human lymphoblastoid CESS cells.
  • Stimulation of CESS cells with calcium ionophore A23187.
  • Western blot analysis for enzyme expression (COX-1, COX-2, 15-LO-1).
  • Treatment with a FLAP inhibitor and aspirin.

Main Results:

  • 5-LO-derived 5(S)-hydroperoxy-eicosatetraenoic acid (5(S)-HETE) significantly increased upon stimulation.
  • A concomitant increase in 4-oxo-2(E)-nonenal-derived DNA adducts (HepsilondGuo) was observed.
  • FLAP inhibition reduced both 5(S)-HETE and HepsilondGuo adducts to basal levels.
  • Aspirin inhibited prostaglandin and HETE formation but not HepsilondGuo adducts.

Conclusions:

  • The 5-lipoxygenase (5-LO) pathway is directly responsible for the generation of HepsilondGuo DNA adducts in CESS cells.
  • FLAP plays a critical role in the 5-LO-mediated formation of these genotoxic adducts.
  • These findings highlight the link between LOX activity and DNA damage, with implications for cancer research.