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Journal Articles Nature Cell Biology Year : 2012

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

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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.

Dates and versions

pasteur-03236097 , version 1 (26-05-2021)

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Moussa Benhamed, Utz Herbig, Tao Ye, Anne Dejean, Oliver Bischof. Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nature Cell Biology, 2012, 14 (3), pp.266-275. ⟨10.1038/ncb2443⟩. ⟨pasteur-03236097⟩
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