Sa1765 Role of Poly(ADP-ribose) Polymerase 1 (PARP1) in the Modulation of Neutrophil Function: Relevance in Inflammatory Bowel Diseases

Larmonier, Claire B.; Shehab, Kareem W.; McFadden, Rita-Marie T.; Kiela, Pawel R.

doi:10.1016/s0016-5085(15)31081-7

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“…Neutrophils carry DNA repair proteins including OGG1, PCNA, PARP, and DNA pol β [18][19][20][21] . For example, DNA helix clamping protein PCNA is stored in the cytoplasm 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Damaged bases could also be repaired independently of the transcription machinery. These include 8-Oxoguanine glycosylase (OGG1), proliferating cell nuclear antigen (PCNA), apurinic/apyrimidinic endonuclease (APE) 1, poly-adenosine diphosphate (ADP) ribose polymerase (PARP), DNA ligase, and DNA repair polymerases (pol) β and δ [18][19][20][21] . Various pathways exist to repair damaged bases (e.g., base excision repair (BER), or nucleotide excision repair (NER) 17 ).…”

Section: Introductionmentioning

confidence: 99%

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ROS induces NETosis by oxidizing DNA and initiating DNA repair

2021

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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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“…Neutrophils carry DNA repair proteins including OGG1, PCNA, PARP, and DNA pol β [18][19][20][21] . For example, DNA helix clamping protein PCNA is stored in the cytoplasm 19 .…”

Section: Discussionmentioning

confidence: 99%