Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

By F. Rodier, Jean-Philippe Coppé, C. Patil, W. Hoeijmakers, Denise P. Muñoz, Saba R. Raza, Adam Freund, E. Campeau, Albert R. Davalos, J. Campisi. Nature Cell Biology, 2009

2,520 citations recorded by the source corpus.

In animals, P-bodies or GW-bodies appear to cause the congregation of proteins involved in microRNA (miRNA)-mediated post-transcriptional silencing. The localization of P-bodies does not overlap with that of known organelles and are thus considered independent of lipid bilayers. Nonetheless, an miRNA effector protein, argonaute 2 (AGO2), was initially identified as membrane-associated, and some miRNAs have been found in secreted vesicles (exosomes) that derive from endo-lysosomal compartments called multivesicular bodies (MVBs). Proteins can be sorted in a ubiquitin-dependent manner into MVBs by three heteromeric subcomplexes, collectively termed ESCRT (endosomal sorting complex required for transport), to be further secreted in exosomes and/or degraded by the lysosome. Here we show that GW-bodies containing GW182 and AGO2, two main components of the RNA-induced silencing complex (RISC), are distinct from P-bodies due to their congregation with endosomes and MVBs. Moreover, miRNAs and miRNA-repressible mRNAs are enriched at these cellular membranes, suggesting that endosomes and/or MVBs are sites of miRNA-loaded RISC (miRISC) accumulation and, possibly, action. We further show that purified exosome-like vesicles secreted by MVBs are considerably enriched in GW182, but not P-body components, AGO2 or miRNA-repressible mRNA. Moreover, cells depleted of some ESCRT components show compromised miRNA-mediated gene silencing and over-accumulate GW182, which associates with ubiquitylated proteins. Therefore, GW182, possibly in association with a fraction of miRNA-loaded AGO2, is sorted into MVBs for secretion and/or lysosomal degradation. We propose that this process promotes continuous assembly or disassembly of membrane-associated miRISCs, which is possibly required for miRNA loading or target recognition and subsequent silencing.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7d299659da10a638510694f1d2aa8800315e4f2a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. J. Campisi
2. Ruben Garcia-Martin
3. Zhijian J. Chen
4. Jesús Gil
5. F. Rodier
6. R. Kahn
7. Tuo Li
8. R. G. Ludwig

In Molecular Biology

1. J. Campisi
2. M. Demaria
3. Jesús Gil
4. Adam Freund
5. B. Hinz
6. F. Rodier
7. Zhijian J. Chen
8. Domhnall McHugh

Citations in the corpus

• The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 (2015, background): “Thus, GATA4 appears to function independently of p53 and the p16/Rb pathway in regulating senescent phenotypes, consistent with the observation that the SASP is p53- and p16-independent (2, 10, 20, 26).”
• Aging, Cellular Senescence, and Cancer (2012, background): “These nuclear structures contain the activated DDR proteins that ensure the persistent DDR signaling (43) that is needed for both the senescence growth arrest and the SASP (32, 42, 43).”
• The essence of senescence. (2010, background): “A recent study indicates that, for the induction of several of these SASP factors, persistent DNA damage is required.”
• Role of interleukin-6 in cancer progression and therapeutic resistance (2016, background): “sistent DNA damage response has been shown to induce IL-6 secretion in stromal cells such as fibroblasts [148].”
• MicroRNA control of signal transduction (2010, neutral): “This is intriguing because signalling and endocytic pathways are intimately intertwined: by regulating endosomal trafficking, signalling cues may tune RISC functio”
• Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “DNA damage (Rodier et al., 2009), p38α MAPK (Freund et al.”
• The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression (2010, background): “Whereas cells induced to senesce by replicative exhaustion, telomere disruption, X-irradiation, or chromatin disruption seem to express closely related SASPs (18, 59), fibroblasts induced to senesce by oncogenic RAS oversecrete more GM-CSF, IL-6, -7, -8, -1β, -13, and GROα than do cells induced to s”
• Immunity, Inflammation, and Cancer (2010, neutral): “Accumulation of damaged DNA and cell senescence can also give rise to tumor-promoting chronic inflammation (Rodier et al., 2009; Zheng et al., 2007).”