Author: ["Moussa Benhamed","Utz Herbig","Tao Ye","Anne Dejean","Oliver Bischof"]
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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. Cellular senescence is partly caused by RB1/E2F-mediated repression of proliferation genes. Bischof and colleagues now demonstrate that RB1 interacts with the microRNA effector AGO2, and that AGO2 and the microRNA let-7 are needed for chromatin remodelling and repression of E2F-target loci.Cite this article
Benhamed, M., Herbig, U., Ye, T. et al. Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nat Cell Biol 14, 266–275 (2012). https://doi.org/10.1038/ncb2443 