A functional antagonism between let-7 and miR-17 family members relying on sequences outside the seed

The seed is a conserved sequence located at the 5'-end of the miRNA, and its specific pairing with the target mRNA is essential for target regulation. Surprisingly, we observed that miR-106a can bind to targets in place of let-7a despite the entirely different seed sequences.

This binding does not depend on the seed sequence of miR-106a but instead relies on the extensive pairing on its 3'-end that shows homology with the let-7a seed sequence. miR-106a binding does not induce direct regulation of the bound targets. It shields them from seed-mediated pairing with let-7 family members, leading to competition for pairing with the same sequence in the target mRNA and resulting in two opposing functional outcomes: target repression by let-7a or target shielding by miR-106a.