Controlling Inflammation Through DNA Damage and Repair
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Advanced atherosclerotic plaques demonstrate extensive DNA damage, seen in smooth muscle cells, endothelial cells, macrophages and in circulating cells, and in both nuclei and mitochondria.1 DNA damage includes both single- or double-stranded breaks, deleted sections of DNA, nucleotide modifications, and extrusions of DNA from the nucleus (micronuclei). Reactive oxygen species (ROS) induce a variety of DNA damage, including oxidatively modified bases, apurinic/apyrimidinic sites, and strand breaks. Guanine is the most readily oxidized base, reacting with •OH to generate a reducing neutral radical that reacts with O2, and via electron transfer, forms 8-oxo-7,8-dihydroguanine (8-oxo-G).2 8-oxo-G and its products are the most abundant DNA lesions on oxidative exposure, with 1 to 2/106 residues in nuclear DNA and 1 to 3/105 residues in mitochondrial DNA (mtDNA), and up to 105 8-oxo-G lesions are formed in the cell daily.1 Advanced plaques are characterized by extensive accumulation of 8-oxo-G, seen in both macrophages and smooth muscle cells.3,4 8-oxo-G is primarily repaired by base excision repair by several enzymes, including specific 8-oxo-G DNA glycosylases I5 and II6 (OGG1/2) and the Nei-like (NEIL) glycosylases; the excised DNA is repaired by AP endonucleases before gap filling by polymerases and ligation.
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Although minor DNA damage is associated with transient growth arrest for DNA repair, more extensive DNA damage can lead to several sequelae, including cell senescence and apoptosis, which both promote inflammation. DNA damage, apoptosis, cell senescence, and inflammation are all present in atherosclerosis, suggesting that DNA damage may be a causal factor in these other processes. However, although DNA damage is present in atherosclerosis, it is unclear whether the endogenous levels actually found have any functional consequences. Indeed, mice seem to be able to tolerate high levels of oxidative DNA …