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Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E4961-E4970. doi: 10.1073/pnas.1618732114. Epub 2017 Jun 5.

An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence.

Author information

1
Department of Microbiology, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506; ivmartinez@hsc.wvu.edu joan.steitz@yale.edu.
2
Department of Microbiology, West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506.
3
Department of Biochemistry and Molecular Biology, University of Florida Health Cancer Center, University of Florida, Gainesville, FL 32610.
4
Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
5
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06536; ivmartinez@hsc.wvu.edu joan.steitz@yale.edu.
6
Howard Hughes Medical Institute, Yale University, New Haven, CT 06536.
7
Yale Cancer Center, New Haven, CT 06520.
8
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06536.
9
Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
10
Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510.

Abstract

The reversible state of proliferative arrest known as "cellular quiescence" plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNA-processing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.

KEYWORDS:

(TMG)-cap; XPO1; XPO5; pri-miRNA; quiescence

PMID:
28584122
PMCID:
PMC5488920
DOI:
10.1073/pnas.1618732114
[Indexed for MEDLINE]
Free PMC Article

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