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PNAS 110 (1): 157-162

Copyright © 2013 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Long-lived microRNA–Argonaute complexes in quiescent cells can be activated to regulate mitogenic responses

Scott H. Olejniczaka,1, Gaspare La Roccaa,1, Joshua J. Gruberb, and Craig B. Thompsona,2

aDepartment of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and bAbramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104

Contributed by Craig B. Thompson, November 19, 2012 (sent for review September 13, 2012)

Abstract: Cellular proliferation depends on the integration of mitogenic stimuli with environmental conditions. Increasing evidence suggests that microRNAs play a regulatory role in this integration. Here we show that during periods of cellular quiescence, mature microRNAs are stabilized and stored in Argonaute protein complexes that can be activated by mitogenic stimulation to repress mitogen-stimulated targets, thus influencing subsequent cellular responses. In quiescent cells, the majority of microRNAs exist in low molecular weight, Argonaute protein-containing complexes devoid of essential components of the RNA-induced silencing complex (RISC). For at least 3 wk, this pool of Argonaute-associated microRNAs is stable and can be recruited into RISC complexes subsequent to mitogenic stimulation. Using several model systems, we demonstrate that stable Argonaute protein-associated small RNAs are capable of repressing mitogen-induced transcripts. Therefore, mature microRNAs may represent a previously unappreciated form of cellular memory that allows cells to retain posttranscriptional regulatory information over extended periods of cellular quiescence.

Key Words: signaling • Ago2 • GW182

Author contributions: S.H.O., G.L.R., J.J.G., and C.B.T. designed research; S.H.O., G.L.R., and J.J.G. performed research; S.H.O., G.L.R., and C.B.T. analyzed data; and S.H.O. and C.B.T. wrote the paper.

1S.H.O. and G.L.R. contributed equally to this work.

Conflict of interest statement: C.B.T. is a cofounder of Agios Pharmaceuticals and has financial interest in Agios.

Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE41921).

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1219958110/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: thompsonc{at}mskcc.org.

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