Off-target messenger RNAs of diacylglycerol kinase zeta small interfering RNA (DGKζ siRNA off-targets)

Off-target messenger RNAs (mRNAs) of diacylglycerol kinase zeta (DGKζ) small interfering RNA (siRNA) refer to the collection of transcripts unintentionally regulated by the siRNA guide strand. While the intended therapeutic target is DGKζ—an enzyme that modulates T-cell signaling by converting diacylglycerol to phosphatidic acid—the siRNA can also bind to other mRNAs with partial sequence complementarity (Cancer Research, 2016, 76(8):2128-2140). This binding typically occurs in the 3' untranslated region (UTR) and is driven by the "seed" region of the siRNA, mimicking the natural regulatory mechanism of microRNAs (Nature, 2007, 445:545–548). Such off-target effects can lead to the unintended downregulation of numerous genes, potentially causing cellular toxicity or confounding the interpretation of therapeutic efficacy. In drug development, these unintended interactions represent a significant safety concern and a challenge for ensuring the specificity of RNAi-based therapies. Strategies to minimize these effects include chemical modifications of the siRNA and bioinformatic filtering to avoid sequences with high seed-match frequency in the human transcriptome (Nature Biotechnology, 2003, 21:635–637).

Other names

Seed-mediated off-targetssiRNA-mediated off-target effectsUnintended mRNA silencingSeed-based off-target transcripts

MicroRNA-like silencing via seed-region complementarity (nucleotides 2-8) to the 3' untranslated region (UTR) of non-target mRNAs, leading to translational repression or mRNA degradation (Nature Biotechnology, 2003, 21:635–637).