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Nat Cell Biol. 2012 Feb 26;14(3):266-75. doi: 10.1038/ncb2443.

Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.

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1
Institut Pasteur, Nuclear Organisation and Oncogenesis Unit, Department of Cell Biology and Infection, F-75015 Paris, France.

Abstract

Cellular senescence is a tumour-suppressor mechanism that is triggered by cancer-initiating or promoting events in mammalian cells. The molecular underpinnings for this stable arrest involve transcriptional repression of proliferation-promoting genes regulated by the retinoblastoma (RB1)/E2F repressor complex. Here, we demonstrate that AGO2, RB1 and microRNAs (miRNAs), as exemplified here by let-7, physically and functionally interact to repress RB1/E2F-target genes in senescence, a process that we call senescence-associated transcriptional gene silencing (SA-TGS). Herein, AGO2 acts as the effector protein for let-7-directed implementation of silent-state chromatin modifications at target promoters, and inhibition of the let-7/AGO2 effector complex perturbs the timely execution of senescence. Thus, we identify cellular senescence as the an endogenous signal of miRNA/AGO2-mediated TGS in human cells. Our results suggest that miRNA/AGO2-mediated SA-TGS may contribute to tumour suppression by stably repressing proliferation-promoting genes in premalignant cancer cells.

PMID:
22366686
DOI:
10.1038/ncb2443
[Indexed for MEDLINE]
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