Oxidative stress-induced retinal damage up-regulates DNA polymerase gamma and 8-oxoguanine-DNA-glycosylase in photoreceptor synaptic mitochondria.
Bright light triggers biphasic photoreceptor nuclear DNA fragmentation, suggesting a DNA-repair response (Invest Ophthalmol Vis Sci 43:3511; 2002; Adv Med Biol 533:229-240; Mol Neurobiol 28:111-122). Here, we demonstrate a remarkable increase in expression of the mitochondrial DNA-repair enzymes, DNA polymerase gamma and 8-oxoguanine-DNA-glycosylase, following bright light treatment in rats. DNA polymerase gamma and 8-oxoguanine, the product of guanine oxidation, were selectively localized in photoreceptor synaptic terminals only within the superior central retinal region, where most light damage occurred. All induced DNA polymerase gamma was localized in photoreceptor synaptic terminals after 5 hr of light exposure, despite the fact that most photoreceptor cell mitochondria are confined to the inner segments. The neuroprotective platelet-activating factor-receptor antagonist LAU-0901 decreased mitochondrial DNA polymerase gamma up-regulation, suggesting that its neuroprotective effect is exerted upstream from this event. During aging, the ability to repair damaged photoreceptor DNA greatly declines. Thus, DNA-repair enzymes such as polymerase gamma and 8-oxoguanine-DNA-glycosylase may provide novel pharmacologic targets to promote DNA repair and rescue photoreceptors in retinal degenerative diseases.
Department of Ophthalmology and Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, School of Medicine in New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA.
M Soledad
MS
Cortina
William C
WC
Gordon
Walter J
WJ
Lukiw
Nicolas G
NG
Bazan
D000375:Aging / Q000235:genetics; D000818:Animals; D045647:DNA Glycosylases / Q000378:metabolism*; D000074002:DNA Polymerase gamma; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology* / Q000648:ultrastructure; D018384:Oxidative Stress; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D013569:Synapses / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects
D004095:Dihydropyridines; C487837:LAU 0901; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C483741:OGG1 protein, rat