Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells
Open accessAbstract
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.
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Silencing these E2F target genes is required for senescence initiation.
“Silencing these E2F target genes is required for senescence initiation.”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Benhamed et al., 2012
The Results sections on E2F-target repression show that these genes are silenced during senescence and that AGO2 contributes to their repression. But the section “AGO2-deficiency regulates the onset of senescence” reports only a delay when AGO2 was depleted; the cells still became senescent. The paper therefore does not establish that silencing these genes is required for senescence initiation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredArgonaute 2 binds let-7f in the nucleus, forming a complex with RB1, resulting in repressive chromatin at CDC2 and CDCA8 promoters.
“For example, Argonaute 2 (AGO2) binds let-7f in the nucleus, forming a complex with RB1 (pRB), resulting in repressive chromatin at CDC2 and CDCA8 promoters (Benhamed et al., 2012).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Benhamed et al., 2012
Argonaute (AGO2), microRNA (let-7) and RB1 interact in the nucleus to repress certain E2F target genes such as CDC2 and CDCA8 during senescence.
“Moreover Argonaute (AGO2), microRNA (let-7) and RB1 interact in the nucleus to repress certain E2F target genes such as CDC2 and CDCA8 during senescence (Benhamed et al., 2012).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Benhamed et al., 2012
Nuclear localized miRISC regulates both transcriptional rates and post-transcriptional levels of mRNA and associates with euchromatin at gene loci with active transcription.
“Nuclear localized miRISC was found to regulate both transcriptional rates and post-transcriptional levels of mRNA (59–61) and associate with euchromatin at gene loci with active transcription (62).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [60]
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- Authors
- Benhamed, M., Herbig, U., Ye, T., Dejean, A., & Bischof, O.
- Affiliations
- Institut Pasteur (FR)
- Rutgers New Jersey Medical School (US)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Inserm (FR)
- Corresponding author
- Dejean, Anne
- Bischof, Oliver
- Venue
- Nature Cell Biology
- Published
- 2012-02-26
- Volume
- 14
- Issue
- 3
- Pages
- 266-275
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC5423543
- OpenAlex
- W2028941546
- Cited by
- 252
- References
- 39
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 15 · 2022: 17 · 2021: 12 · 2020: 17 · 2019: 19 · 2018: 12 · 2017: 20 · 2016: 22 · 2015: 19 · 2014: 29 · 2013: 26 · 2012: 15
- FWCI
- 19.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Cancer Institute (R01CA136533)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- cellular senescence, transcriptional silencing, microRNA, Argonaute 2, let-7 microRNA, RB1, E2F transcription factors, tumor suppression, chromatin remodeling
- MeSH terms
- Base Sequence, Binding Sites, Cell Line, Cell Nucleus, Heterochromatin, Humans, Mutation, Promoter Regions, Genetic, Protein Binding, Blotting, Western, Signal Transduction, Retinoblastoma Protein, Cellular Senescence, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Silencing, Gene Expression Profiling, MicroRNAs, Cell Line, Tumor, Chromatin Immunoprecipitation, E2F Transcription Factors, Argonaute Proteins
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