PT  - JOURNAL ARTICLE
AU  - Quan Q. Gao
AU  - William E. Putzbach
AU  - Andrea E. Murmann
AU  - Siquan Chen
AU  - Aishe A. Sarshad
AU  - Johannes M. Peter
AU  - Elizabeth T. Bartom
AU  - Markus Hafner
AU  - Marcus E. Peter
TI  - 6mer seed toxicity in tumor suppressive microRNAs
AID  - 10.1101/284406
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 284406
4099  - http://biorxiv.org/content/early/2018/07/11/284406.short
4100  - http://biorxiv.org/content/early/2018/07/11/284406.full
AB  - Many small interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (position 2–7 of the guide strand). A siRNA screen with all 4096 possible 6mer seed sequences in a neutral siRNA backbone revealed a preference for guanine in positions 1 and 2 and a high overall G or C content in the seed of the most toxic siRNAs for four tested human and mouse cell lines. Toxicity of these siRNAs stems from targeting survival genes with C-rich 3’UTRs. The master tumor suppressor miRNA miR-34a-5p is toxic through such a G-rich 6mer seed and is upregulated in cells subjected to genotoxic stress. In the absence of most canonical miRNAs, a modified highly toxic form of miR-320a-3p is induced. An analysis of all mature miRNAs suggests that during evolution most miRNAs evolved to avoid guanine at the 5’ end of the 6mer seed sequence of the guide strand. In contrast, for certain tumor suppressive miRNAs the guide strand contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.