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The Journal of Cell Biology, Vol. 181, No. 7, 1055-1063
The Rockefeller University Press, 0021-9525 $30.00
© Mudhasani et al.
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Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells

Rajini Mudhasani1, Zhiqing Zhu1, Gyorgy Hutvagner2, Christine M. Eischen4, Stephen Lyle3, Lisa L. Hall1, Jeanne B. Lawrence1, Anthony N. Imbalzano1, and Stephen N. Jones1,3

1 Departments of Cell Biology, 2 Biochemistry and Molecular Pharmacology, and 3 Cancer Biology, University of Massachusetts Medical School, North Worcester, MA 01655
4 Department of Pathology, Vanderbilt University School of Medicine, South Nashville, TN 37232

Correspondence to Stephen N. Jones: stephen.jones{at}

Dicer, an enzyme involved in microRNA (miRNA) maturation, is required for proper cell differentiation and embryogenesis in mammals. Recent evidence indicates that Dicer and miRNA may also regulate tumorigenesis. To better characterize the role of miRNA in primary cell growth, we generated Dicer-conditional mice. Ablation of Dicer and loss of mature miRNAs in embryonic fibroblasts up-regulated p19Arf and p53 levels, inhibited cell proliferation, and induced a premature senescence phenotype that was also observed in vivo after Dicer ablation in the developing limb and in adult skin. Furthermore, deletion of the Ink4a/Arf or p53 locus could rescue fibroblasts from premature senescence induced by Dicer ablation. Although levels of Ras and Myc oncoproteins appeared unaltered, loss of Dicer resulted in increased DNA damage and p53 activity in these cells. These results reveal that loss of miRNA biogenesis activates a DNA damage checkpoint, up-regulates p19Arf-p53 signaling, and induces senescence in primary cells.

R. Mudhasani and Z. Zhu contributed equally to this paper.

Abbreviations used in this paper: Ad, adenovirus; dpi, days post induction; ES, embryonic stem; FACS, fluorescence-activated cell sorting; MEF, mouse embryonic fibroblast; miRNA, microRNA; SA-βgal, senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatin foci; wt, wild type.

© 2008 Mudhasani et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

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