Recent evidence has shown that the let-7 miRNA bites the hand that feeds it . . . and in an unconventional way. By searching for short sequences conserved at the nucleotide level in the coding regions of 17 species, Hilary Coller and co-workers at Princeton University identified three let-7 target sites within the coding sequence of the miRNA-processing enzyme Dicer. Dicer completes the final cleavage step of miRNA, after which mature miRNA in the RISC complex targets partially complementary mRNA for translational inhibition. Proving that no good deed goes unpunished, the let-7miRNA strongly down-regulates Dicer in a negative feedback loop by binding within the coding region, as demonstrated by Coller and colleagues.
Previously, functional miRNA target sites were thought to occur only in the 3’ untranslated regions (3’ UTRs) of animal mRNA transcripts. However, these findings establish that miRNA-binding sites in coding regions, which have been conserved through hundreds of millions of years of evolution, can function in posttranscriptional repression. In addition to let-7, three other miRNA target sites (miR-9, miR-125a, and miR-153) were found to be highly conserved within coding regions of the human genome. Because the target sites in coding regions exhibited different miRNA base pairing preferences than those in 3’ UTRs, the two types of miRNA target sites might inhibit translation by different mechanisms. Check out all the details in PNAS, September 2008