PT  - JOURNAL ARTICLE
AU  - William Putzbach
AU  - Quan Q. Gao
AU  - Monal Patel
AU  - Stijn van Dongen
AU  - Ashley Haluck-Kangas
AU  - Aishe A. Sarshad
AU  - Elizabeth Bartom
AU  - Kwang-Youn A. Kim
AU  - Denise M. Scholtens
AU  - Markus Hafner
AU  - Jonathan C. Zhao
AU  - Andrea E. Murmann
AU  - Marcus E. Peter
TI  - Toxic si/shRNAs that kill cancer cells by targeting survival genes
AID  - 10.1101/141952
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 141952
4099  - http://biorxiv.org/content/early/2017/09/10/141952.short
4100  - http://biorxiv.org/content/early/2017/09/10/141952.full
AB  - 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. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that using specific toxic RNAi-active sequences present in the genome can kill cancer cells.