Dicer has long been known for its ability to produce siRNAs and miRNAs, the guides which drive RNA silencing, from long, double-stranded RNA or miRNA precursors (pre-miRNAs). Kaneko et al. now report a fascinating role for mammalian Dicer, separate from its function in RNA silencing.
In a series of elegant experiments, the authors show a role for mammalian Dicer in preventing the inflammatory changes of geographic atrophy or “dry” age related macular degeneration (AMD) by degrading Alu dsRNA in the retinal pigmented epithelial (RPE) cells of both mice and humans. Interestingly, this effect was due to the endonuclease activity of Dicer alone
degrading dsRNA, independent of siRNA loading in the RNA-induced silencing complex (RISC).
They find that Dicer expression is decreased in the retinal pigmented epithelial cells in patients with geographic atrophy, which allows the accumulation of long dsRNA Alu elements. These repetitive Alu elements produce inflammatory changes leading to the loss of the retinal pigmented epithelium and producing the disease phenotype. The authors were able to recapitulate geographic atrophy in a mouse model by making a tissue-specific knockout of Dicer in the RPE cells. This study highlights a role for Dicer in suppressing repetitive elements beyond the more well studied role of Dicer in producing siRNAs and miRNAs that function as guides for RISC.