Survival-gene messenger RNAs targeted by 6-nucleotide toxic seeds (DISE targets)

Survival-gene messenger RNAs (mRNAs) containing complementary 6-nucleotide (6-nt) toxic seed matches in their 3′ untranslated regions (UTRs) are the collective targets of a biological mechanism known as Death Induced by Survival gene Elimination (DISE). This mechanism is triggered by specific small RNAs, such as certain microRNAs or synthetic siRNAs, that possess a "toxic" 6-mer seed sequence (often G-rich) capable of binding to and downregulating hundreds of genes essential for cell viability simultaneously (Putzbach et al., 2017, eLife). In ovarian cancer cells, these survival genes are frequently overexpressed to maintain rapid proliferation and evade programmed cell death. By targeting the 3' UTRs of these genes through the RNA-induced silencing complex (RISC), DISE-inducing RNAs can bypass traditional drug resistance mechanisms that typically arise when targeting single proteins (Gao et al., 2018, Nature Communications). Therapeutic strategies involve the delivery of synthetic siRNAs or the upregulation of endogenous tumor-suppressive miRNAs like miR-34a to induce widespread transcriptome-wide degradation of survival factors. This approach leads to a unique and potent form of cell death that is difficult for cancer cells to evolve resistance against, although challenges remain regarding the efficient delivery of these RNA therapeutics and ensuring minimal impact on healthy tissues (Murmann et al., 2018, Scientific Reports).

Other names

DISE-sensitive mRNAsSurvival genes targeted by 6-mer seedsDeath Induced by Survival gene Elimination targets6-mer seed targets

RNA interference-mediated degradation of multiple survival genes via 6-mer seed complementarity in 3' UTRs