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 γ and 8-oxoguanine-DNA-glycosylase, following bright light treatment in rats. DNA polymerase γ 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 γ 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 γ 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 γ and 8-oxoguanine-DNA-glycosylase may provide novel pharmacologic targets to promote DNA repair and rescue photoreceptors in retinal degenerative diseases.