DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts

Abstract

SummaryThe 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.

MicroRNA Regulation of Oxidative Stress‐Induced Cellular Senescence

“…Loss of miRNA synthesis through blocking DGCR8 expression in adult C. elegans showed accelerated aging and reduced lifespan [57]. Knockdown of DGCR8 triggered a dramatic antiproliferative response and consequently senescence phenotype characterized by upregulation of p21 in primary fibroblasts of human and mouse origin [58]. In addition, several senescence regulating proteins are reported to regulate DGCR8.…”

Are microRNAs true sensors of ageing and cellular senescence?

“…P53 was also shown to be a downstream target of miR-19b (Fan et al, 2014). MiR-21 may target p21, as it has been shown to reverse the effects of a deletion of DGCR8, the Drosha auxiliary protein, which usually leads to senescence (Gómez-Cabello et al, 2013). Details of miRNAs related to p53 are given in Table 1.…”

“…During senescence, various tumor suppressors and death signals inhibit many of the normal functions of the cell. Common tumor suppressor systems such as p53, p21, and p16 are regulated by miRNA expression (Borgdorff et al, 2010; Gómez-Cabello et al, 2013; Overhoff et al, 2014; Ugalde et al, 2011; Yamakuchi et al, 2008). The role of miRNAs in modulating the expression of pathways leading to cellular senescence has led to an increased focus on their role in induced cell death.…”

miR-421, miR-155 and miR-650: Emerging Trends of Regulation of Cancer and Apoptosis

“…It is cleaved in the nucleus by the microprocessor complex (consisting of the RNase III endonuclease Drosha and the co-factor DGCR8. Recently it has been reported that knockdown of DGCR8 in primary fibroblasts induced senescent phenotype (Gómez-Cabello et al, 2013). Yet another contemporary study revealed that targeted inhibition of DGCR8 remarkably reduced migratory and invasive potential of ovarian cancer cells .…”