Multiple seed-matched messenger RNA 3' untranslated regions (mRNA 3'UTR seed-match sites)

Multiple seed-matched messenger RNA 3' untranslated regions (3'UTRs) refer to the collective set of sequences within the transcriptome that are complementary to the seed region (nucleotides 2-7 or 2-8) of a microRNA (miRNA) or small interfering RNA (siRNA) (Bartel, 2009). These regions serve as the primary docking sites for the RNA-induced silencing complex (RISC), which facilitates post-transcriptional gene silencing through mRNA degradation or translational inhibition (Setten et al., 2019). In therapeutic development, targeting multiple 3'UTRs is a hallmark of miRNA-based drugs, which aim to modulate entire biological pathways rather than single genes. Conversely, unintended binding to multiple seed-matched 3'UTRs is a major source of off-target toxicity in siRNA therapeutics, as a single siRNA can potentially regulate hundreds of transcripts (Grimm, 2009). A specific therapeutic application involves 'Death Induced by Survival gene Elimination' (DISE), where siRNAs are designed to target the 3'UTRs of multiple essential survival genes simultaneously to kill cancer cells (Putzbach et al., 2017). This mechanism is also central to the function of endogenous miRNAs, which maintain cellular homeostasis by fine-tuning the expression of large gene networks. Drugs interacting with these sites include various siRNA and miRNA-based therapeutics currently in clinical use or development, such as Patisiran and Givosiran. Safety concerns primarily involve the potential for widespread off-target effects and the saturation of endogenous RNA processing pathways.

Other names

miRNA seed-match sites3'UTR binding sitesRNAi off-target sitesDISE-associated 3'UTRsSeed-matched mRNA sequences

RNA interference (RNAi) and microRNA-mediated gene silencing via binding to complementary seed sequences in the 3'UTR of target mRNAs, leading to mRNA cleavage or translational repression.