Survival gene messenger RNAs (DISE targets)

Non-E2F1 mRNAs with seed-region complementarity refers to a collective group of messenger RNAs (mRNAs) that are targeted by specific small RNAs to induce a potent form of cell death known as Death Induced by Survival gene Elimination (DISE) (Putzbach et al., 2017). This mechanism was discovered when researchers observed that siRNAs designed to knockdown the E2F1 transcription factor remained toxic even in cells lacking E2F1, due to their 6-nucleotide seed sequences binding to the 3' untranslated regions (UTRs) of numerous essential survival genes (Gao et al., 2018). By simultaneously downregulating multiple pathways required for cell viability, this approach bypasses the common resistance mechanisms cancer cells develop against single-target therapies (Peter et al., 2019). The target is essentially a functional network of survival-critical transcripts rather than a single protein or gene, and it is exploited by both experimental siRNAs and endogenous microRNAs like miR-34a and let-7 (Putzbach et al., 2017). While primarily an experimental concept, it informs the development of miRNA-based therapeutics and explains the off-target toxicity profiles of certain RNA interference (RNAi) drugs (Hadji et al., 2014).

Other names

Non-E2F1 mRNAs with seed-region complementarityDISE-sensitive mRNAs6mer seed targetsSurvival gene network

Induction of Death Induced by Survival gene Elimination (DISE) through RNA-induced silencing complex (RISC)-mediated degradation or translational inhibition of multiple essential survival genes (Putzbach et al., 2017).