microRNA biogenesis and senescence

senescence acts as a physiological barrier against uncontrolled proliferation of cells with potentially harmful alterations, contributing to tumor suppression and tissue homeostasis in live organisms [1]. Senescence is a complex phenotype that involves major changes in cellular function and structure. This phenotype is characterized by a specific gene expression program, which is controlled by key transcriptional regulators as well as by global and gene-specific epigenetic changes. In addition, the post-transcriptional control of senescence mediated by non-coding RNAs has recently attracted much interest [1]. In this context, our recent results [2] provide new evidence that supports the notion that microRNA-mediated control of gene expression plays a critical regulatory role in cellular senescence. MicroRNAs are small noncoding RNAs that negatively regulate gene expression primarily through the degradation or translation inhibition of mRNAs with complementary sequences. To examine the impact of global disruption of miRNA activity in primary cells we focused on DGCR8 (also known as Pasha), an essential factor required for early steps of miRNA synthesis. Together with the ribonuclease DROSHA, DGCR8 forms the so-called Microprocessor nuclear complex, which is responsible of the processing of primary miRNA transcripts to generate the pre-miRNA intermediates that are further processed by Dicer to yield mature miRNAs [3]. We found that the disruption of miRNA biogenesis by silencing of DGCR8 behaved as a potent pro-senescence stimulus in human and mouse primary fibroblasts, leading to a clear reduction in proliferation, and the acquisition of classical senescence markers including flattened morphology, SA-BetaGal activity or formation of SAHF. Silencing of other key miRNA regulators, such as DROSHA or DICER had similar effects, supporting the notion that this phenotype was associated to global disruption of miRNA activity. Our data ruled out that the induction of senescence observed could be due to indirect activation of oncogenes, DNA damage, or global changes in chromatin. Instead, we hypothesized that the silencing of the miRNA regulator DGCR8 could have subverted Editorial the physiological regulation of senescence by miRNAs. In our search for specific candidate miRNAs, we noted a significant overlap between miRNAs down-regulated during MEK-induced senescence and a set of miRNAs previously associated with cell-cycle defects in Dgcr8-defective ES cells [4]. This group of miRNAs included miR-20a, miR-106a and miR-93, a subset of miRNAs from the miR-17-92 family with identical seed sequences, and potentially common downstream targets. Interestingly, the miR-17-92 cluster and its paralogs have oncogenic features, since they are frequently overexpressed in tumors, …