Breakthrough article on mechanistic features of microRNA targeting and activity

Giovanna Brancati and Helge Grosshans from the FMI have described target specialization of miRNAs of the let-7 family. They identified target site features that determine specificity, and revealed that specificity can be modulated in a manner that allows cells to integrate target site quality and miRNA abundance. Their findings address the unresolved question of how miRNA family members can be targeting different transcripts within the same cell. A dogma in the miRNA field has been that the so-called miRNA 'seed' (5') region suffices for target silencing and that, therefore, 'miRNA sisters' function redundantly because they share a seed sequence. However, this view has recently been challenged through experimental target capture, which indicated extensive specialization of individual miRNA family members through seed-distal (miRNA 3' end) pairing. In their studies published as a Breakthrough Article in Nucleic Acids Research (NAR), the investigators determined experimentally features that govern specialization of members of the let-7 family, which are popular model miRNAs with important functions in development and tumorigenesis. Through in vivo studies in C. elegans , they found that extensive seed-distal pairing promotes specificity, but that the extent of specificity is modest, and insufficient to support robust development, unless target sites also contain an imperfect seed match.