RT Journal Article
SR Electronic
T1 Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 141952
DO 10.1101/141952
A1 William Putzbach
A1 Quan Q. Gao
A1 Monal Patel
A1 Stijn van Dongen
A1 Ashley Haluck-Kangas
A1 Aishe A. Sarshad
A1 Elizabeth Bartom
A1 Kwang-Youn A. Kim
A1 Denise M. Scholtens
A1 Markus Hafner
A1 Jonathan C. Zhao
A1 Andrea E. Murmann
A1 Marcus E. Peter
YR 2017
UL http://biorxiv.org/content/early/2017/09/14/141952.abstract
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.