Regulation in Reserve

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Science Signaling  08 Jan 2013:
Vol. 6, Issue 257, pp. ec7
DOI: 10.1126/scisignal.2003943

When deprived of nutrients or growth factors, cells can survive by altering their metabolism, reducing gene expression and protein synthesis, and entering a quiescent state. Mitogenic signals stimulate gene expression that induces mitotic “recovery,” or reentry into the cell cycle. However, mitogenic signaling is associated with an increase in transcriptional load, a stressful state for a quiescent cell with reduced metabolic capacity. Arsenite resistance protein 2 (Ars2), which stimulates the expression of histone mRNAs and small, noncoding RNAs called microRNAs, functions during mitogenic-induced recovery. Following an unexpected finding that short-interfering RNA (siRNA) targeting Ars2 was stable and delayed mitogen-induced recovery for at least 3 weeks after a single transient transfection in quiescent cells, Olejniczak et al. found that endogenous microRNAs miR-23, miR-26, and miR-21 were stably stored in low-molecular-weight complexes with Argonaute, the catalytic component of the RNA-induced silencing complex (RISC), during periods of quiescence induced with withdrawal of growth factors. Mitogenic stimulation of the quiescent cells increased the abundance of the RISC component GW182 and induced its assembly into high-molecular-weight complexes with Argonaute. Association of the Argonaute-microRNA complex with RISC resulted in the translational repression of miR-21 targets, indicating that the previously sequestered microRNAs were functional. Exogenous siRNAs were also stored and reactivated through this mechanism, similar to endogenous microRNAs. Furthermore, the proportion of mature, processed microRNAs relative to global RNA concentration increased over a long period of mitogen withdrawal, whereas the abundance of primary microRNA precursors decreased. Together, the data indicate that repression of target mRNAs was accomplished by mature microRNAs that are reactivated from long-term storage in Argonaute complexes after mitogen-induced RISC assembly rather than through de novo expression. The stored and then released microRNAs may function to limit the production of some proteins in quiescent cells responding to mitogenic signals and thereby direct limited resources toward translating mRNAs that are critical to mitotic recovery.

S. H. Olejniczak, G. La Rocca, J. J. Gruber, C. B. Thompson, Long-lived microRNA–Argonaute complexes in quiescent cells can be activated to regulate mitogenic responses. Proc. Natl. Acad. Sci. U.S.A. 110, 157–162 (2013). [Abstract] [Full Text]

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