Cited by 204Neutrophil, Myeloperoxidase and Oxidative MechanismsRedox biology and oxidative stressBlood disorders and treatments

ROS induces NETosis by oxidizing DNA and initiating DNA repair

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Azzouz, Dhia, Khan, Meraj A., Palaniyar, Nades·2021·Cell Death Discovery

Abstract

Reactive oxygen species (ROS) are essential for neutrophil extracellular trap (NET) formation or NETosis. Nevertheless, how ROS induces NETosis is unknown. Neutrophil activation induces excess ROS production and a meaningless genome-wide transcription to facilitate chromatin decondensation. Here we show that the induction of NADPH oxidase-dependent NETosis leads to extensive DNA damage, and the subsequent translocation of proliferating cell nuclear antigen (PCNA), a key DNA repair protein, stored in the cytoplasm into the nucleus. During the activation of NETosis (e.g., by phorbol myristate acetate, Escherichia coli LPS, Staphylococcus aureus (RN4220), or Pseudomonas aeruginosa ), preventing the DNA-repair-complex assembly leading to nick formation that decondenses chromatin causes the suppression of NETosis (e.g., by inhibitors to, or knockdown of, Apurinic endonuclease APE1, poly ADP ribose polymerase PARP, and DNA ligase). The remaining repair steps involving polymerase activity and PCNA interactions with DNA polymerases β/δ do not suppress agonist-induced NETosis. Therefore, excess ROS produced during neutrophil activation induces NETosis by inducing extensive DNA damage (e.g., oxidising guanine to 8-oxoguanine), and the subsequent DNA repair pathway, leading to chromatin decondensation.

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Authors
Azzouz, D., Khan, M. A., & Palaniyar, N.
Affiliations
  • University of Toronto (CA)
  • Hospital for Sick Children (CA)
Corresponding author
Palaniyar, Nades
Venue
Cell Death Discovery
Published
2021-05-18
Volume
7
Issue
1
Pages
113-113
ISSN
2058-7716 (ISSN-L)
OpenAlex
W3163218484
Cited by
202
References
35
Citations by year
2026: 37 · 2025: 61 · 2024: 50 · 2023: 22 · 2022: 28 · 2021: 4
FWCI
9.89
Type
journal article
Language
en
Open access
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cystic Fibrosis Canada (3180)
  • Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (RGPIN436250-13)
  • Gouvernement du Canada | Canadian Institutes of Health Research (MOP-111012)
  • Hospital for Sick Children
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
neutrophil extracellular traps, NETosis, reactive oxygen species, NADPH oxidase, DNA damage, DNA repair, chromatin decondensation, 8-oxoguanine, APE1, poly(ADP-ribose) polymerase, DNA ligase, neutrophil activation, DNA polymerase beta, DNA polymerase delta

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