부산대학교 도서관

The regulation of gene expression by micro RNAs (mi RNAs) is critical for normal development and physiology. Conversely, mi RNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual mi RNAs or dysregulation of mi RNA synthesis. Here, we have investigated the impact of global disruption of mi RNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical mi RNAs. 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 p21 CIP1. We further show that a subset of senescence-associated mi RNAs with the potential to target p21 CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to mi RNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical micro RNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific mi RNAs, and thus identify global mi RNA disruption as a novel senescence trigger. [ABSTRACT FROM AUTHOR]