Cytoplasmic synthesis of endogenous complementary DNA via reverse transcription and implications in age-related macular degeneration.

retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether cDNA is synthesized independently of genomic integration is unknown. RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed cDNA independently of retrotransposition. RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. reverse transcription can be initiated in the cytoplasm via self-priming of RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this replication cycle shunt as potential therapies for a major cause of blindness.