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Elife. 2018 Oct 16;7. pii: e38621. doi: 10.7554/eLife.38621.

CD95/Fas ligand mRNA is toxic to cells.

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Department of Medicine, Division Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States.
Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, United States.
Contributed equally


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). We now report expression of full-length CD95L mRNA itself is highly toxic to cells and induces a similar form of cell death. We demonstrate that small (s)RNAs derived from CD95L are loaded into the RNA induced silencing complex (RISC) which is required for the toxicity and processing of CD95L mRNA into sRNAs is independent of both Dicer and Drosha. We provide evidence that in addition to the CD95L transgene a number of endogenous protein coding genes involved in regulating protein translation, particularly under low miRNA conditions, can be processed to sRNAs and loaded into the RISC suggesting a new level of cell fate regulation involving RNAi.


DISE; Fas; RISC; RNAi; cancer biology; human

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