Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Open accessAbstract
Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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Many senescence triggers activate DNA damage response signaling and p53/p21, p16/RB or other pathways, producing cell cycle arrest and a SASP.
“Many such stressors activate DNA damage response signaling and activation of the p53/p21CIP1/WAF1, p16INK4a/retinoblastoma protein or other pathways, resulting in cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP)24,40,48−53”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [50]
The paper’s Abstract (page unavailable in our copy) supports a pathway from persistent DNA damage signalling to p53-dependent growth arrest and a senescence-associated inflammatory cytokine response. It does not support the sentence’s implication that the p53/p21 or p16/RB arrest pathways themselves produce that response: it reports that the cytokine response is p53-independent and that p16-induced senescence without DNA damage does not initiate it. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere is substantial overlap among SASPs, with proinflammatory cytokines being the most highly conserved feature across many cell types and senescence-inducing stimuli.
“Nevertheless, there is substantial overlap among SASPs; proinflammatory cytokines are the most highly conserved feature, cutting across many different cell types and senescence-inducing stimuli (33, 42, 96, 99, 100, 112–114).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
The passages labeled Abstract report IL-6 and IL-8 secretion in several fibroblast models and under multiple DNA-damaging conditions. They do not compare SASPs to establish that proinflammatory cytokines are their most highly conserved feature; the paper also reports that p16-induced senescence without DNA damage did not initiate a cytokine response. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe SASP is primarily a property of cells that senesce due to or accompanied by genomic damage or epigenomic perturbation.
“The SASP is primarily a property of cells that senesce owing to, or accompanied by, genomic damage or epigenomic perturbation.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
In the supplied copy’s Abstract (page not specified), persistent DNA damage correlates with secretion of inflammatory SASP factors, while p16-induced senescence without DNA damage does not initiate that cytokine response. The paper says DNA-damage signalling drives only a subset of SASP factors; it does not establish the claim for the SASP as a whole or address epigenomic perturbation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDNA-SCARS and TIF contain activated DDR proteins that ensure persistent DDR signaling needed for both the senescence growth arrest and the SASP.
“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).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
The indexed main text (page not supplied) reports that persistent DNA damage foci contain activated ATM and are associated with sustained DDR signaling; its model links that signaling to senescence growth arrest and inflammatory cytokine secretion. But the paper calls these structures persistent DNA damage foci, rather than specifically establishing the claim for both DNA-SCARS and TIF, and it says DDR signaling regulates only a subset of SASP factors, not the entire SASP. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDDR proteins stimulate the SASP only after persistent DDR signaling has been established.
“Of particular importance, these DDR proteins stimulate the SASP only after persistent DDR signaling has been established.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
The paper’s discussion of its model (page unavailable) says persistent DDR signaling initiates the cytokine response after several days through ATM, NBS1 and CHK2. But its analysis of SASP factors says DDR signaling regulates only a subset, including IL-6 and IL-8, not the SASP as a whole. (LLM, conf=0.85)
Experimental — accuracy not yet measured
p53 inactivation in cells that do not express p16INK4a causes cells to resume proliferation while the SASP remains active.
“Furthermore, p53 inactivation in cells that do not express p16INK4a, which renders the senescence growth arrest irreversible (10), causes cells to resume proliferation, but the SASP remains active (32, 42).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
The passage on p53 inactivation in senescent HCA2 cells (section labeled Abstract; page unavailable) reports that growth arrest reversed while IL-6 secretion persisted and increased. It describes the cells as expressing low levels of p16INK4a, however, not as having no p16INK4a expression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe rapid robust DDR immediately after DNA damage does not induce a SASP; the SASP develops slowly over several days in culture and only after the initial DDR subsides.
“That is, the rapid robust DDR that occurs immediately after DNA damage does not induce a SASP; rather, the SASP develops slowly—over several days in culture—and only after the initial DDR subsides (32, 42).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
In the indexed passage labeled Abstract (page unavailable), the paper reports that IL-6 and IL-8 secretion rises over 2–5 days after high-dose irradiation, rather than immediately, and links the response to persistent DNA-damage signalling. It does not establish that the SASP begins only after the initial DDR subsides; it says DDR signalling persists and helps initiate the delayed cytokine response. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMany but not all SASP components are positively regulated by the DDR proteins ATM, NBS1, and CHK2.
“Many, but not all, SASP components are positively regulated by the DDR proteins ATM, NBS1 (Nijmegen breakage syndrome 1), and CHK2 (checkpoint kinase 2) (42, 67).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
The paper’s passage on SASP factors (section labelled Abstract; page unavailable) reports that ATM depletion reduced 7 of 16 measured factors, while 9 were unchanged. Its passage on NBS1 and CHK2 shows that depleting either suppressed IL-6 secretion, but does not establish that either regulates many SASP components. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCells that senesce due to DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals, oxidative stress, and other stimuli develop a SASP of varying qualities and robustness.
“In contrast, cells that senesce owing to DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals, oxidative stress, and other senescence-inducing stimuli develop a SASP of varying qualities and robustness (32, 33, 42, 67, 94, 96, 99, 100, 112–114).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
The paper reports SASP-associated cytokine secretion after persistent DNA damage, dysfunctional telomeres, and oncogenic RAS expression (sections on replicative senescence and oncogene-induced senescence; page numbers unavailable). It also shows that secretion varies with the stimulus: p16-induced senescence without DNA damage produced little IL-6. Our copy does not establish SASP development after epigenomic disruption or oxidative stress, so it does not support the full list of stimuli. (LLM, conf=0.88)
Experimental — accuracy not yet measuredATM, NBS1 and CHK2 prime SASP genes for activation, and depleting these upstream DDR regulators reduces cytokine production after genotoxic stress.
“ATM, NBS1 and CHK2 prime SASP genes for activation, as depletion of these DDR upstream regulators dampens cytokine production in response to genotoxic stress86”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [86]
The passage labeled Abstract (page unavailable; Figs. 4–5) reports that depleting ATM, NBS1 or CHK2 prevented the irradiation-induced increase in IL-6 secretion, and that ATM depletion reduced secretion of several SASP factors. It supports their role in initiating the cytokine response, but does not establish that they prime SASP genes for activation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredp53 limits SASP gene expression.
“Because p53 also limits SASP gene expression (Coppé et al., 2008; Rodier et al., 2009), we depleted p53 in WT and rho0 cells and measured IL1A and IL1B mRNA levels.”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Rodier et al., 2009
The passage describing the p53-inactivation experiments (section labelled Abstract; page unavailable) reports that loss of p53 increased secreted IL-6 in HCA2 fibroblasts, consistent with p53 limiting at least one SASP factor. It measures cytokine secretion, however, not SASP gene expression generally or the IL1A and IL1B mRNA levels mentioned in the citing sentence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIR robustly activates p53, which subsides to a low chronic level in 7-10 days as the SASP develops.
“IR robustly activates p53, which subsides to a low chronic level in 7–10 days as the SASP develops (Coppé et al., 2008; Rodier et al., 2009).”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Rodier et al., 2009
The passage labeled Abstract (page unavailable; Fig. 1a–c) reports rapid p53 activation after irradiation, and another passage reports that inflammatory cytokine secretion develops after a delay following a senescence-inducing dose. It does not establish that p53 subsides to a low chronic level at 7–10 days: the reported return toward baseline within 10 hours concerns a low dose from which cells recovered, while cytokine secretion reached senescent levels within 3–5 days. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA signature pro-inflammatory secretory phenotype takes 7-10 days to develop under DDR.
“A signature pro-inflammatory secretory phenotype takes 7–10 days to develop under DDR (Coppe et al, 2008; Rodier et al, 2009).”
From Feedback between p21 and reactive oxygen production is necessary for cell senescence (2010) · cites this paper as Rodier et al, 2009
The passage discussing Fig. 1e (indexed under Abstract; page unavailable) supports a delayed inflammatory response under persistent DDR, but not a 7–10-day development time: IL-6 and IL-8 secretion increased within 2–4 days and reached replicatively senescent levels within 3–5 days. A later passage reports a response measured at 9–10 days, which does not establish that it took that long to develop. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA full senescent phenotype develops over 7-10 days in human fibroblasts.
“Own (Supplementary Figure S1A) and published (Coppe et al, 2008; Rodier et al, 2009) data indicated that a full senescent phenotype develops over 7–10 days in human fibroblasts.”
From Feedback between p21 and reactive oxygen production is necessary for cell senescence (2010) · cites this paper as Rodier et al, 2009
The paper reports senescence-associated growth arrest and cytokine secretion in human fibroblasts, including an IL-6 response measured 9–10 days after irradiation (main text, Fig. 4b; page unavailable). It does not say that a full senescent phenotype takes 7–10 days to develop; it reports that IL-6 and IL-8 secretion reached replicatively senescent levels within 3–5 days (main text, Fig. 1e; page unavailable). (LLM, conf=0.82)
Experimental — accuracy not yet measuredSASP is composed of pro-inflammatory cytokines, chemokines, exosomes, growth factors, and extracellular matrix-degrading proteins released into surrounding tissue following induction of growth arrest.
“The SASP is composed of pro-inflammatory cytokines, chemokines, exosomes, growth factors, and extracellular matrix-degrading proteins that are released into the surrounding tissue environment following the induction of growth arrest.24,25,26,27,28,29”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [27]
The paper’s Abstract describes the SASP as a secretory phenotype and identifies inflammatory cytokines IL-6 and IL-8; it also names MMP3 as another SASP factor. It does not establish the full listed composition, particularly exosomes, chemokines and growth factors. Its findings also qualify the timing: inflammatory secretion can occur in cycling cells without growth arrest, while arrest induced without DNA damage did not produce the cytokine response (Abstract; page unavailable). (LLM, conf=0.87)
Experimental — accuracy not yet measuredExpression of CDK inhibitors p16 or p21 leads to induction of senescence without development of a DDR, and this senescent phenotype lacks a proinflammatory SASP.
“In addition, expression of the CDK inhibitors p16 or p21 leads to the induction of senescence without the development of a DDR; this senescent phenotype lacks a proinflammatory SASP (Rodier et al. 2009).”
From Cellular senescence and its effector programs (2014) · cites this paper as Rodier et al. 2009
The passage describing the p16INK4a experiment (labelled Abstract; page unavailable, Fig. 1f–g) reports senescence arrest with few persistent DNA-damage foci and little IL-6 or IL-8 secretion. The paper does not report the same experiment or conclusion for p21; it mentions p21 as a response to irradiation, so the claim's extension to p21 is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLoss of ATM or other DNA damage response factors such as NBS1 and CHK2 leads to reductions in some SASP factors such as IL6 and IL8 during DDR-induced senescence and oncogene-induced senescence.
“Loss of ataxia telangiectasia-mutated (ATM) or other factors responding to DNA damage (such as NBS1 and CHK2) leads to reductions in some SASP factors, such as IL6 and IL8, central components of SASP, during not only DDR-induced senescence but also OIS (Rodier et al. 2009).”
From Cellular senescence and its effector programs (2014) · cites this paper as Rodier et al. 2009
The supplied passages (labeled Abstract; Figs. 4h–i and 5b) report that ATM, NBS1 and CHK2 depletion reduced IL-6 secretion after irradiation, and that ATM depletion also reduced IL-8. The OIS passage (Fig. 5h–i) shows reduced IL-6 secretion with ATM depletion, but does not establish the same OIS result for NBS1 or CHK2, or for IL-8. No page numbers were provided. (LLM, conf=0.87)
Experimental — accuracy not yet measuredInduction of p21 and a Notch-driven SASP are considered early events, whereas upregulation of p16INK4a and an NF-κB-driven SASP are evident at later stages of senescence.
“Induction of p21 and a Notch- driven SASP are considered early events 70,75,76 , whereas upregulation of p16 INK4a and an NF- κB- driven SASP are evident at later stages of senescence 71,77,78 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [78]
The passage on radiation-induced senescence (section labelled Abstract; page unavailable) reports that inflammatory cytokine secretion develops after a delay, supporting a later-emerging inflammatory SASP. It does not establish that p16INK4a is upregulated later or that the later SASP is NF-κB-driven; the passages also do not address early p21 induction or a Notch-driven SASP. (LLM, conf=0.79)
Experimental — accuracy not yet measuredAlkylating agents, topoisomerase inhibitors, γ-irradiation, microtubule inhibitors and, to a lesser extent, vinca alkaloids have all been identified as senescence inducers in preclinical models.
“Alkylating agents 27,95,96 (for example, cisplatin, cyclophosphamide and temozolomide), topoisomerase inhibitors 27,65,91,95 (such as doxorubicin, etoposide and camptothecin) and γ- irradiation 78 , but also microtubule inhibitors 27,97,98 (for example, paclitaxel) and, to a lesser extent, vinca alkaloids 78 (for example, vincristine), have all been identified as senescence inducers in preclinical”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [78]
The paper reports that 10 Gy X-irradiation induced senescence in human fibroblasts (Abstract; page unavailable), supporting the broader point that ionizing radiation can induce senescence in a preclinical model. It specifies X-rays rather than γ-irradiation, and the passages found do not support the vinca-alkaloid example also attached to this citation. The other drug classes in the citing sentence carry different citations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredp53 negatively regulates or restrains the SASP.
“In contrast to positive regulation by the DDR, p53 negatively regulates or, more accurately, restrains the SASP (32, 42) (Figure 2).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [42]
SASP is promoted by DDR and can promote DDR and TAF formation in autocrine and paracrine fashion.
“SASP is both promoted by DDR13 and can promote DDR and TAF formation in an autocrine and paracrine fashion14–16.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [13]
p53 inhibition enhances SASP after a senescence-inducing insult, which may create an inflammatory microenvironment favouring senescence escape and malignant transformation.
“Inhibition of p53 has the opposite effect, as it further enhances SASP following a senescence-inducing insult86, which may contribute to the generation of an inflammatory microenvironment that favours senescence escape and malignant transformation”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [86]
Persistent DNA damage response signalling is often required to initiate inflammatory cytokine secretion.
“persistent DDR signalling is often required to initiate inflammatory cytokine secretion86”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [86]
Persistent DDR activity is required for the induction of several proinflammatory SASP factors, such as IL-6 and IL-8.
“Persistent DDR activity is required for the induction of several proinflammatory SASP factors, such as IL-6 and IL-8 (Rodier et al. 2009).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Rodier et al. 2009
Dysfunctional mitochondria, persistent DNA damage response, C/EBPβ and NF-κB, mTOR, and other factors are involved in regulating SASP.
“Furthermore, dysfunctional mitochondria,195 persistent DNA damage response,196 CCAAT/enhancer-binding protein β (C/EBPβ) and NF-κB,197 mTOR, and other factors are involved in regulating SASP.194”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [196]
Senescent cells induced by genotoxic stress, replicative exhaustion, or oncogenic stress secrete factors associated with inflammation, proliferation, and modulation of the extracellular matrix.
“Senescent cells induced by either genotoxic stress, replicative exhaustion, or oncogenic stress secrete myriad factors associated with inflammation, proliferation, and modulation of the extracellular matrix (ECM) (Acosta et al. 2008; Kuilman et al. 2008; Rodier et al. 2009).”
From Cellular senescence and its effector programs (2014) · cites this paper as Rodier et al. 2009
DDR-independent senescence has been reported in some experimental conditions where p16, p38MAPK, or ATR is constitutively activated or Pten is completely lost.
“Of note, DDR-independent senescence has also been reported in some experimental conditions where p16, p38MAPK, or ATR is constitutively activated or tumor suppressor Pten is completely lost (Toledo et al. 2008; Rodier et al. 2009; Alimonti et al. 2010; Freund et al. 2011).”
From Cellular senescence and its effector programs (2014) · cites this paper as Rodier et al. 2009
Senescent cells undergo dramatic changes in gene expression.
“Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Rodier et al., 2009
Senescent cells undergo chromatin remodeling and engage a persistent DNA damage response (DDR).
“They undergo dramatic gene expression changes along with chromatin remodeling and engagement of a persistent DNA damage response (DDR) (Rodier et al., 2009; Wang et al., 2009; Sulli et al., 2012; Chandra et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Rodier et al., 2009
DNA damage, dysfunctional telomeres, genomic damage, epigenomic perturbation, mitogenic proliferative signals, oxidative stress or other senescence-inducing stimuli, all leading to prolonged DDR, express SASP to different extents.
“DNA damage, dysfunctional telomeres, genomic damage, epigenomic perturbation, mitogenic proliferative signals, oxidative stress or other senescence-inducing stimuli, all leading to prolonged DDR express SASP to different extents (Acosta et al., 2008; Kuilman et al., 2008; Rodier et al., 2009; Coppé et al., 2010b; Pazolli et al., 2012).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Rodier et al., 2009
DNA damage activates DDR, a p53/21-dependent response that is originally transient but can become persistent if damage is severe enough, and can also be reversed through p16/pRB pathways.
“In general terms, DNA damage activates DDR, a p53/21-dependent response that is originally transient but which can become persistent if the damage is severe enough, and which can also be reversed through the p16/pRB pathways [219], [241].”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [241]
The SASP does not depend on p53 or p16INK4a, suggesting that it is controlled by a separate branch of the senescence regulatory network.
“the SASP does not depend on either p53 or p16INK4a, which suggests that it is controlled by an independent branch of the senescence regulatory network (2, 10, 20, 26).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [20]
Senescent cells acquire a senescence-associated secretory phenotype, secreting factors that disrupt microenvironments and compromise tissue structure and function, contributing to ageing pathologies and cancer.
“However, senescent cells acquire a “senescence-associated secretory phenotype” (SASP), secreting many pro-inflammatory cytokines, proteases, and growth and angiogenesis factors that can disrupt microenvironments and compromise tissue structure and function thereby contributing to local and systemic ageing-associated pathologies47 and promote cancer64.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [47]
Cellular senescence in vitro may occur without detectable DNA damage response.
“although cellular senescence in vitro may also occur without detectable DDR [31,32].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [32]
Tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells.
“In addition, tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells [51, 53, 58–63].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [62]
Cell cycle controlling proteins p16, p21, and p53 normally inhibit cell cycle progression and accumulate in senescent cells.
“Cell cycle controlling proteins p16, p21, and p53, normally inhibit cell cycle progression and have been shown to be accumulated in senescent cells [49–51].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [50]
Cellular senescence is a primary aging process and tumor suppressive mechanism with features including irreversible growth arrest, apoptosis resistance, SASP, mitochondrial dysfunction, and DNA/chromatin changes.
“Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [22]
Hallmarks of cellular senescence include irreversible growth arrest, SASP, apoptosis resistance, mitochondrial dysfunction, persistent DNA damage foci, and epigenetic remodeling including senescence-associated heterochromatin foci.
“Hallmarks of the cellular senescence phenotype include irreversible growth arrest, a senescence-associated secretory phenotype (SASP) (Box 1), apoptosis resistance, mitochondrial dysfunction [21], persistent DNA damage foci [22] and epigenetic remodeling, which includes formation of senescence-associated heterochromatin foci [23].”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [22]
The p53-dependence of CCL2 production may distinguish CCL2 from some of the other chemokines produced in senescent cells, which are dependent on the senescent state but are produced independently of p53.
“The p53-dependence of CCL2 production may distinguish CCL2 from some of the other chemokines produced in senescent cells, which are dependent on the senescent state but are produced independently of p53 (Coppé et al., 2008; Rodier et al., 2009).”
From p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells (2013) · cites this paper as Rodier et al., 2009
Senescent cells secrete different inflammatory cytokines and chemokines depending on whether senescence is induced by genotoxic stress or mitochondrial dysfunction.
“Senescent cells secrete a distinct suite of inflammatory cytokines and chemokines depending upon whether senescence is induced by genotoxic stress, [23] or mitochondrial dysfunction, as in the form of deficiencies in mitochondrial sirtuins or damage to mitochondrial DNA [24]”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [23]
Senescent cells are programmed to secrete different chemokines, pro-inflammatory cytokines, growth factors, and matrix-remodeling enzymes that define the SASP.
“In addition to the downregulation of cell cycle genes, senescent cells are programmed to secrete different chemokines, pro-inflammatory cytokines, growth factors, and matrix-remodeling enzymes that define the SASP [136,147,148].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [148]
Activation of the SASP program requires a sustained DDR signal but is independent of p53, p21, and p16.
“Activation of the SASP program requires a sustained DDR signal but is independent of p53, p21, and p16 (the mediators of cell cycle arrest in senescent cells) [147,148].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [148]
ATM signaling is required for the secretion of IL-6 and IL-8, the most conserved and robustly expressed inflammatory cytokines, but does not regulate the entire production of SASP factors.
“ATM signaling does not regulate the entire production of SASP factors, although it is required for the secretion of IL-6 and IL-8, the most conserved and robustly expressed inflammatory cytokines [148].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [148]
SASP factor production requires continuous DNA damage signaling.
“SASP factor production requires continuous DNA damage signaling [148].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [148]
The secretome of senescent tumor cells can drive tumor progression by promoting inflammation and potentially stimulating growth and invasiveness of nearby tumor cells.
“the secretome of senescent tumor cells can also drive tumor progression by promoting inflammation and potentially stimulating the growth and invasiveness of nearby tumor cells [148,154,163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [148]
DNA damage is a potent activator of inflammatory signaling and senescence.
“DNA damage is a potent activator of inflammatory signaling and senescence (Coppé et al, 2008; Rodier et al, 2009; Brzostek‐Racine et al, 2011; Härtlova et al, 2015).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Rodier et al, 2009
Persistent DDR signaling in fibroblasts, bone marrow-derived macrophages, and primary monocytes elicits the senescence-associated secretory phenotype.
“Initially, induction of persistent DDR signaling in cell cultures including fibroblasts (Coppé et al, 2008; Rodier et al, 2009), bone marrow‐derived macrophages (BMDMs) (Härtlova et al, 2015), and primary monocytes (Brzostek‐Racine et al, 2011) was found to elicit the SASP (Coppé et al, 2008).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Rodier et al, 2009
The SASP induced by persistent DDR signaling is at least partially ATM-dependent.
“This secretory profile was found to be at least partially ATM‐dependent, implying the importance of DSB repair specifically in immune activation (Rodier et al, 2009; Brzostek‐Racine et al, 2011).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Rodier et al, 2009
These SASP factors are part of the IL-1-dependent inflammatory arm.
“These SASP factors are part of the IL-1-dependent inflammatory arm57, and are normally expressed by DNA damage-induced senescent cells.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [57]
These SASP factors are normally expressed by DNA damage-induced senescent cells.
“These SASP factors are part of the IL-1-dependent inflammatory arm57, and are normally expressed by DNA damage-induced senescent cells.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [57]
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Self-citationp53-dependent integration of telomere and growth factor deprivation signals
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Immunity, Inflammation, and Cancer
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- Authors
- Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J.
- Affiliations
- Lawrence Berkeley National Laboratory (US)
- Buck Institute for Research on Aging (US)
- Corresponding author
- Campisi, Judith
- Venue
- Nature Cell Biology
- Published
- 2009-07-13
- Volume
- 11
- Issue
- 8
- Pages
- 973-979
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2743561
- OpenAlex
- W2116054786
- Cited by
- 2,232
- References
- 31
- Citations by year
- 2026: 126 · 2025: 143 · 2024: 152 · 2023: 158 · 2022: 159 · 2021: 168 · 2020: 154 · 2019: 147 · 2018: 139 · 2017: 149 · 2016: 113 · 2015: 105 · 2014: 118 · 2013: 102 · 2012: 108
- FWCI
- 64.86
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-10-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG017242, P30AG025708, AG025708, P01AG017242)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- DNA damage response, senescence-associated secretory phenotype, IL-6 secretion, oncogene-induced senescence, ATM, NBS1, Chk2, DNA double-strand breaks, tumour invasiveness, senescence-associated inflammation, p53, retinoblastoma protein
- MeSH terms
- Cell Line, Cells, Cultured, DNA Damage, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Fibroblasts, Humans, Male, Microscopy, Fluorescence, Nuclear Proteins, Transfection, Blotting, Western, Signal Transduction, Interleukin-6, Tumor Suppressor Protein p53, Cytokines, Telomere, Cellular Senescence, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, RNA, Small Interfering, Green Fluorescent Proteins, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
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