Open AccessDGCR 8‐mediated disruption of mi RNA biogenesis induces cellular senescence in primary fibroblasts
Author(s) -
GómezCabello Daniel,
Adrados Isabel,
Gamarra David,
Kobayashi Hikaru,
Takatsu Yoshihiro,
Takatsu Kyoko,
Gil Jesús,
Palmero Ignacio
Publication year - 2013
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12117
Subject(s) - biology , senescence , microrna , microbiology and biotechnology , biogenesis , gene knockdown , downregulation and upregulation , cell cycle , phenotype , cell cycle checkpoint , cell , cancer research , genetics , cell culture , gene
Summary The regulation of gene expression by micro RNA s (mi RNA s) 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 RNA s 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 DGCR 8, an essential mediator of the synthesis of canonical mi RNA s. We find that the inactivation of DGCR 8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR 8 loss is accompanied by the upregulation of the cell‐cycle inhibitor p21 CIP 1. We further show that a subset of senescence‐associated mi RNA s with the potential to target p21 CIP 1 is downregulated during DGCR 8‐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 RNA s results in cell‐cycle arrest and cellular senescence in primary fibroblasts mediated by specific mi RNA s, and thus identify global mi RNA disruption as a novel senescence trigger.