Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer's disease and aging.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a cell death mechanism mediated by short (s) RNAs acting through the RNA-induced silencing complex (RISC). DISE is thus a form of RNA interference, in which G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich 6mer seed matches in genes essential for cell survival, resulting in the activation of cell death pathways.

CD95/Fas ligand mRNA is toxic to cells through more than one mechanism.

CD95/Fas ligand (CD95L) induces apoptosis through protein binding to the CD95 receptor. However, CD95L mRNA also induces toxicity in the absence of CD95 through induction of DISE (Death Induced by Survival Gene Elimination), a form of cell death mediated by RNA interference (RNAi). We now report that CD95L mRNA processing generates a short (s)RNA nearly identical to shL3, a commercial CD95L-targeting shRNA that led to the discovery of DISE.

CD95/Fas ligand induced toxicity.

The role of CD95/Fas ligand (CD95L/FasL) in the induction of CD95-mediated extrinsic apoptosis is well characterized. Trimerized, membrane-bound CD95L ligates the CD95 receptor activating downstream signaling resulting in the execution of cells by caspase proteins. However, the expression of CD95L has been reported to induce cell death in contexts in which this pathway is unlikely to be activated, such as in cell autonomous activation induced cell death (AICD) and in CD95-resistant cancer cell lines.

SPOROS: A pipeline to analyze DISE/6mer seed toxicity.

microRNAs (miRNAs) are (18-22nt long) noncoding short (s)RNAs that suppress gene expression by targeting the 3' untranslated region of target mRNAs. This occurs through the seed sequence located in position 2-7/8 of the miRNA guide strand, once it is loaded into the RNA induced silencing complex (RISC). G-rich 6mer seed sequences can kill cells by targeting C-rich 6mer seed matches located in genes that are critical for cell survival.

DISE/6mer seed toxicity-a powerful anti-cancer mechanism with implications for other diseases.

micro(mi)RNAs are short noncoding RNAs that through their seed sequence (pos. 2-7/8 of the guide strand) regulate cell function by targeting complementary sequences (seed matches) located mostly in the 3' untranslated region (3' UTR) of mRNAs. Any short RNA that enters the RNA induced silencing complex (RISC) can kill cells through miRNA-like RNA interference when its 6mer seed sequence (pos.

CD95/Fas ligand mRNA is toxic to cells.

CD95/Fas ligand binds to the death receptor CD95 to induce apoptosis in sensitive cells. We previously reported that CD95L mRNA is enriched in sequences that, when converted to si/shRNAs, kill all cancer cells by targeting critical survival genes (Putzbach et al., 2017).

DISE: A Seed-Dependent RNAi Off-Target Effect That Kills Cancer Cells.

Off-target effects (OTEs) represent a significant caveat for RNAi caused by substantial complementarity between siRNAs and unintended mRNAs. We now discuss the existence of three types of seed-dependent OTEs (sOTEs). Type I involves unintended targeting through the guide strand seed of an siRNA.

Induction of DISE in ovarian cancer cells .

The death receptor CD95/Fas can be activated by immune cells to kill cancer cells. shRNAs and siRNAs derived from CD95 or CD95 ligand (CD95L) are highly toxic to most cancer cells. We recently found that these sh/siRNAs kill cancer cells in the absence of the target by targeting the 3'UTRs of critical survival genes through canonical RNAi.

Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism.

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3'UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death.