title: Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.
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.
authors.affiliation: Institut Pasteur, Nuclear Organisation and Oncogenesis Unit, Department of Cell Biology and Infection, F-75015 Paris, France.
authors.forename: Moussa
authors.initials: M
authors.lastname: Benhamed
authors.forename: Utz
authors.initials: U
authors.lastname: Herbig
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
authors.forename: Oliver
authors.initials: O
authors.lastname: Bischof
mesh_terms: D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D050684:E2F Transcription Factors; D006570:Heterochromatin; D035683:MicroRNAs; D016160:Retinoblastoma Protein; C487931:mirnlet7 microRNA, human