6mer seed toxicity in tumor suppressive microRNAs

Quan Q. Gao; William E. Putzbach; Andrea E. Murmann; Siquan Chen; Aishe A. Sarshad; Johannes M. Peter; Elizabeth T. Bartom; Markus Hafner; Marcus E. Peter

doi:10.1038/s41467-018-06526-1

6mer seed toxicity in tumor suppressive microRNAs

Quan Q. Gao, William E. Putzbach, Andrea E. Murmann, Siquan Chen, Aishe A. Sarshad, Johannes M. Peter, Elizabeth T. Bartom, Markus Hafner, Marcus E. Peter^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing 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. 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.

Original language	English (US)
Article number	4504
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06526-1
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-06526-1

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title = "6mer seed toxicity in tumor suppressive microRNAs",

abstract = "Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing 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. 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.",

author = "Gao, {Quan Q.} and Putzbach, {William E.} and Murmann, {Andrea E.} and Siquan Chen and Sarshad, {Aishe A.} and Peter, {Johannes M.} and Bartom, {Elizabeth T.} and Markus Hafner and Peter, {Marcus E.}",

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doi = "10.1038/s41467-018-06526-1",

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AU - Gao, Quan Q.

AU - Putzbach, William E.

AU - Murmann, Andrea E.

AU - Chen, Siquan

AU - Sarshad, Aishe A.

AU - Peter, Johannes M.

AU - Bartom, Elizabeth T.

AU - Hafner, Markus

AU - Peter, Marcus E.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing 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. 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.

AB - Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing 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. 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.

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6mer seed toxicity in tumor suppressive microRNAs

Abstract

ASJC Scopus subject areas

UN SDGs

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