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Abstract
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.
Highlights
Tumors arise as a consequence of the malfunction of critical regulators of normal cellular homeostasis, which results in aberrant proliferation and other tumor-associated traits
We find that disrupted microRNA synthesis results in a senescence-like antiproliferative response in primary fibroblasts, as a consequence of the deregulation of key miRNAs linked to the cell-cycle machinery, and this response is essentially retained in tumor cell lines
Early-passage IMR90 human primary fibroblasts were infected with vectors expressing shRNAs against DGCR8, which efficiently reduced endogenous DGCR8 mRNA and protein levels (Fig. 1A, left and Fig. S1A)
Summary
Tumors arise as a consequence of the malfunction of critical regulators of normal cellular homeostasis, which results in aberrant proliferation and other tumor-associated traits. In recent years, it has become increasingly clear the essential role of regulatory noncoding RNAs, such as microRNAs (miRNAs) or long noncoding RNAs (lncRNAs) in Accepted for publication 09 June 2013 cancer and other human pathologies. These regulatory RNAs play a key role in the control of cellular functions critically altered in tumor formation and progression, and their deregulation is an almost universal feature of tumors (Esteller, 2011; Lujambio & Lowe, 2012). We find that disrupted microRNA synthesis results in a senescence-like antiproliferative response in primary fibroblasts, as a consequence of the deregulation of key miRNAs linked to the cell-cycle machinery, and this response is essentially retained in tumor cell lines
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