PT  - JOURNAL ARTICLE
AU  - Quan Q. Gao
AU  - William E. Putzbach
AU  - Andrea E. Murmann
AU  - Siquan Chen
AU  - Giovanna Ambrosini
AU  - Johannes M. Peter
AU  - Elizabeth T. Bartom
AU  - Marcus E. Peter
TI  - 6mer Seed Toxicity Determines Strand Selection in miRNAs
AID  - 10.1101/284406
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 284406
4099  - http://biorxiv.org/content/early/2018/03/19/284406.short
4100  - http://biorxiv.org/content/early/2018/03/19/284406.full
AB  - Many siRNAs and shRNAs 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 RNA backbone revealed a preference for guanine in positions 1-3 and a GC content of >80% of the 6mer seed in the most toxic siRNAs. These 6mer seed containing siRNAs exert their toxicity by targeting survival genes which contain GC-rich 3’UTRs. The master tumor suppressor miRNA miR-34a was found to be toxic through such a G-rich 6mer seed suggesting that certain tumor suppressive miRNAs use a toxic 6mer seed to kill cancer cells. An analysis of all mature miRNAs suggests that most miRNAs evolved to avoid guanine at the 5′ end of the 6mer seed sequence of the predominantly expressed arm. In contrast, for many tumor suppressive miRNAs the predominant arm contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.