These authors contributed equally.
DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts
Article first published online: 19 JUL 2013
© 2013 The Anatomical Society and John Wiley & Sons Ltd
Volume 12, Issue 5, pages 923–931, October 2013
How to Cite
Gómez-Cabello, D., Adrados, I., Gamarra, D., Kobayashi, H., Takatsu, Y., Takatsu, K., Gil, J. and Palmero, I. (2013), DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts. Aging Cell, 12: 923–931. doi: 10.1111/acel.12117
- Issue published online: 11 SEP 2013
- Article first published online: 19 JUL 2013
- Accepted manuscript online: 17 JUN 2013 02:43AM EST
- Manuscript Accepted: 9 JUN 2013
- Spanish Government to IP. Grant Numbers: SAF2009-09031, SAF2012-32117
The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.