RT Journal Article SR Electronic T1 CD95L derived si- and shRNAs and the CD95L mRNA kill cancer cells through an RNAi mechanism by targeting survival genes JF bioRxiv FD Cold Spring Harbor Laboratory SP 141952 DO 10.1101/141952 A1 William Putzbach A1 Quan Q. Gao A1 Monal Patel A1 Aishe A. Sarshad A1 Abbas Hadji A1 Stijn van Dongen A1 Ashley Haluck-Kangas A1 Elizabeth Bartom A1 Austin Stults A1 Abdul S. Qadir A1 Kwang-Youn A. Kim A1 Markus Hafner A1 Jonathan C. Zhao A1 Andrea E. Murmann A1 Marcus E. Peter YR 2017 UL http://biorxiv.org/content/early/2017/06/16/141952.abstract AB >80% of a large number of siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death that is characterized by the simultaneous activation of multiple death pathways and preferentially affects transformed and cancer stem cells. We now show that 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. By testing 4666 shRNAs derived from the CD95 and CD95L mRNAs and an unrelated control gene, Venus, we have located the most toxic sequences in the open reading frame of CD95L. Consistently, CD95L mRNA is highly toxic to cancer cells after complete deletion of CD95. Our data provide the first evidence for mRNAs to affect cell fate through RNAi in mammalian cells. In addition, they suggest that cancer cells can be targeted with specific toxic RNAi active sequences present in the genome.