Other mRNAs with partial seed complementarity

Other mRNAs with partial seed complementarity refers to a broad class of unintended genetic targets that are silenced by small interfering RNAs (siRNAs) or microRNAs (miRNAs) through sequence-specific interactions. This phenomenon, often termed "seed-mediated off-target effects," occurs when the seed region of the oligonucleotide guide strand (nucleotides 2-8) binds to complementary sequences in the 3' untranslated regions (UTRs) of non-target mRNAs (Jackson et al., 2003, Nature Biotechnology). Once bound, these off-target mRNAs are processed by the RNA-induced silencing complex (RISC), resulting in mRNA degradation or the inhibition of protein translation. In the field of oligonucleotide therapeutics, these interactions are a primary source of sequence-specific toxicity and can lead to adverse clinical outcomes such as hepatotoxicity (Janas et al., 2018, Nature Communications). To minimize these risks, drug developers employ chemical modifications, such as 2'-O-methyl substitutions at the second nucleotide of the guide strand, to destabilize off-target binding while maintaining on-target potency. Understanding and predicting these interactions through bioinformatic screening is a critical component of the safety assessment for any RNA-based therapeutic (Setten et al., 2019, Nature Reviews Drug Discovery).

Other names

Off-target mRNAsSeed-mediated off-targetsmiRNA-like off-target effectsTranscriptome-wide off-targets

The guide strand of an siRNA or miRNA incorporates into the RNA-induced silencing complex (RISC) and utilizes its "seed region" (nucleotides 2-8) to bind via partial complementarity to the 3' untranslated regions (UTRs) of unintended mRNAs, leading to their degradation or translational repression (Birmingham et al., 2006, Nature Methods; Jackson et al., 2003, Nature Biotechnology).