Mechanisms and Regulation of Cellular Senescence

In the paper

“The delayed ARF expression increase probably reflects the complex organization of the responsive elements within the ARF promoter [130,131,132].”

What the sources say

• Partly supported

  The Discussion describes several potential Sp1 and E2F binding sites and other promoter regions important for ARF transcription, supporting the description of a complex promoter. The expression analysis reports time-dependent ARF induction after 5-aza-CdR treatment, but the paper does not attribute a delayed increase to the arrangement of promoter response elements; in that experiment, ARF expression slightly preceded INK4a expression. Page numbers were not available in our copy. (LLM, conf=0.85)

  cites [130] Robertson, 1998, The Human ARF Cell Cycle Regulatory Gene Promoter Is a CpG Island Which Can Be Silenced by DNA Methylation and Down-Regulated by Wild-Type p53, Mol. Cell. Biol. sourceExperimental — accuracy not yet measured
• Not checked yetcites [131] Inoue, 1999, Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1, Proc. Natl. Acad. Sci. USA source
• Partly supported

  The sections on E2F1 activation describe multiple responsive regions in the p14 ARF promoter, including non-canonical sites, supporting the claim that its regulation is complex. The paper does not link that organization to a delayed increase in ARF expression; a search for delay and response timing found no such explanation. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  cites [132] Berkovich, 2003, E2F and Ras Synergize in Transcriptionally Activating p14ARFExpression, Cell Cycle sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  The paper reports that senescent-cell secretions include inflammatory cytokines and can stimulate cancer-cell growth and invasion; its invasion assay found that medium from senescent cells increased breast cancer-cell invasiveness (main text, indexed under Abstract). However, the cells studied as the source of these secretions were primarily fibroblasts (Materials and Methods, Cells), so the paper does not establish the claim specifically for senescent tumor cells. (LLM, conf=0.86)

  cites [148] Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) links oncogene-induced senescence to inflammatory cytokines and says senescent cells can supply promitogenic IL-6. The paper also reports that secreted IL-6 stimulated proliferation in B9 hybridoma cells, but it does not establish increased invasiveness or growth of nearby tumor cells. Its discussion of secreted factors promoting tumorigenesis concerns senescent fibroblasts, not specifically senescent tumor cells. (LLM, conf=0.87)

  cites [154] Kuilman, 2008, Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network, Cell sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (page unavailable) says the senescence-associated secretory phenotype (SASP) contains inflammatory cytokines, may contribute to inflammation, and can promote malignant phenotypes in nearby cells. The Results section (page unavailable) reports that conditioned media from senescent fibroblasts stimulated prostate cancer cell proliferation, migration and invasion, and that these fibroblasts promoted tumour growth. Although the Abstract says tumour cells can also develop a SASP, the reported tumour-promoting experiments used senescent fibroblasts, not the secretome of senescent tumour cells. (LLM, conf=0.88)

  cites [163] Laberge, 2015, MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation, Nat. Cell Biol. sourceExperimental — accuracy not yet measured

In the paper

“This capacity requires changes in core cellular programs.”

In the paper

“The proliferative arrest imposed by cellular senescence represents an early barrier against cancer initiation by preventing the propagation of damaged DNA to the next generation of cells [18,20].”

What the sources say

• Not checked yetcites [18] Collado, 2005, Senescence in premalignant tumours, Nature source
• Not checked yetcites [20] Weinberg, 2005, The signals and pathways activating cellular senescence, Int. J. Biochem. Cell Biol. source

In the paper

“Senescence can also be triggered by many other intrinsic and extrinsic factors, particularly, replicative stress, oxidative damage, metabolism dysfunctions, cytokines, oncogene activation, and chemotherapy agents.”

What the sources say

• Not checked yetcites [6] 2008, Living on a break: Cellular senescence as a DNA-damage response, Nat. Rev. Cancer source

In the paper

“Senescence is an important contributor to cancer and aging, two processes characterized by a time-dependent accumulation of cell damage and dysfunction.”

What the sources say

• Not checked yetcites [16] 2017, The Fountain of Youth by Targeting Senescent Cells?, Trends Mol. Med. source

In the paper

“Cellular senescence occurs not only in vitro (i.e., cell culture models), but also in various tissues in vivo [13,14,15,16].”

What the sources say

• Not checked yetcites [13] Baker, 2016, Naturally occurring p16Ink4a-positive cells shorten healthy lifespan, Nature source
• Not checked yetcites [14] Chang, 2016, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice, Nat. Med. source
• Not checked yetcites [15] Yosef, 2016, Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL, Nat. Commun. source
• Not checked yetcites [16] 2017, The Fountain of Youth by Targeting Senescent Cells?, Trends Mol. Med. source

In the paper

“Moreover, stem cell senescence caused by telomere shortening can negatively affect tissue homeostasis and regeneration [25].”

What the sources say

• Not checked yetcites [25] Ju, 2007, Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment, Nat. Med. source

In the paper

“Senescence markers are detected in premalignant tumor lesions but not at later stages of tumor development [17,18,19].”

What the sources say

• Not checked yetcites [17] Chen, 2005, Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis, Nature source
• Not checked yetcites [18] Collado, 2005, Senescence in premalignant tumours, Nature source
• Not checked yetcites [19] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source

In the paper

“Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions.”

What the sources say

• Not checked yetcites [13] Baker, 2016, Naturally occurring p16Ink4a-positive cells shorten healthy lifespan, Nature source
• Not checked yetcites [14] Chang, 2016, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice, Nat. Med. source
• Not checked yetcites [15] Yosef, 2016, Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL, Nat. Commun. source
• Not checked yetcites [16] 2017, The Fountain of Youth by Targeting Senescent Cells?, Trends Mol. Med. source

In the paper

“During aging, senescent cell accumulation in various tissues promotes chronic inflammation that accelerates age-related dysfunctions [16].”

What the sources say

• Not checked yetcites [16] 2017, The Fountain of Youth by Targeting Senescent Cells?, Trends Mol. Med. source

In the paper

“On the other hand, senescent fibroblasts can influence their local environment by turning into proinflammatory cells that can promote the growth of transformed or preneoplastic neighboring epithelial cells in culture and in vivo [22,23,24].”

What the sources say

• Not checked yetcites [22] Krtolica, 2001, Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [23] Parrinello, 2005, Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation, J. Cell Sci. source
• Not checked yetcites [24] Campisi, 2013, Aging, Cellular Senescence, and Cancer, Annu. Rev. Physiol. source

In the paper

“Senescent cells present unique morphological and molecular characteristics and functions that distinguish them from other nondividing cell populations, such as quiescent cells and terminally differentiated cells [4,5,6].”

What the sources say

• Not checked yetcites [4] Campisi, 2007, Cellular senescence: When bad things happen to good cells, Nat. Rev. Mol. Cell Biol. source
• Not checked yetcites [5] Collado, 2007, Cellular Senescence in Cancer and Aging, Cell source
• Not checked yetcites [6] 2008, Living on a break: Cellular senescence as a DNA-damage response, Nat. Rev. Cancer source

In the paper

“Persistent activation of RB prevents G1 to S phase progression by sequestering E2F transcription factors.”

In the paper

“It is generally thought that the growth arrest of senescent cells occurs through a cell cycle blockade in the G1 phase to prevent DNA replication initiation in damaged cells [4,6].”

What the sources say

• Not checked yetcites [4] Campisi, 2007, Cellular senescence: When bad things happen to good cells, Nat. Rev. Mol. Cell Biol. source
• Not checked yetcites [6] 2008, Living on a break: Cellular senescence as a DNA-damage response, Nat. Rev. Cancer source

In the paper

“Importantly, p21 depletion ameliorates the regenerative capacity of proliferative tissues, such as the intestine and hematopoietic stem cells, in late-generation telomerase-deficient mice that experience telomere shortening and age-related degeneration [43].”

What the sources say

• Not checked yetcites [43] Choudhury, 2007, Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation, Nat. Genet. source

In the paper

“High p21 or p16 expression level is sufficient to induce cell cycle arrest in early-passage human fibroblasts in culture [35,36].”

What the sources say

• Not checked yetcites [35] McConnell, 1998, Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts, Curr. Biol. source
• Not checked yetcites [36] Rodier, 2011, Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype, J. Biol. Chem. source

In the paper

“Therefore, entry into senescence and the long-term cell cycle exit are regulated through different changes in gene expression, metabolism, and cell organization.”

In the paper

“Compared with p21, p16 accumulation is relatively slow in replicatively senescent fibroblasts [38,39].”

What the sources say

• Not checked yetcites [38] Alcorta, 1996, Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [39] Stein, 1999, Differential Roles for Cyclin-Dependent Kinase Inhibitors p21 and p16 in the Mechanisms of Senescence and Differentiation in Human Fibroblasts, Mol. Cell. Biol. source

In the paper

“Indeed, unlike chronic senescence (i.e., accumulation of deleterious senescent cells with aging), the acute induction of cellular senescence represents a transient physiological response during embryonic development [27,28] and adult tissue homeostasis (e.g., to facilitate tissue repair after liver damage, in skin fibrosis, and wound healing) [29,30,31].”

What the sources say

• Not checked yetcites [27] Maraver, 2013, Programmed Cell Senescence during Mammalian Embryonic Development, Cell source
• Not checked yetcites [28] Storer, 2013, Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning, Cell source
• Not checked yetcites [29] Krizhanovsky, 2008, Senescence of Activated Stellate Cells Limits Liver Fibrosis, Cell source
• Not checked yetcites [30] Jun, 2010, The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing, Nat. Cell Biol. source
• Not checked yetcites [31] Demaria, 2014, An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA, Dev. Cell source

In the paper

“CDK regulation through the expression of CDK inhibitors, including p21 (CDKN1A), p15 (CDKN2B), and p16 (CDKN2A), is of special relevance in all senescence types.”

In the paper

“Rodent and human senescent cells in culture and in many tissues typically display high levels of these proteins during normal aging [37,38,39].”

What the sources say

• Not checked yetcites [37] Noda, 1994, Cloning of Senescent Cell-Derived Inhibitors of DNA Synthesis Using an Expression Screen, Exp. Cell Res. source
• Not checked yetcites [38] Alcorta, 1996, Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [39] Stein, 1999, Differential Roles for Cyclin-Dependent Kinase Inhibitors p21 and p16 in the Mechanisms of Senescence and Differentiation in Human Fibroblasts, Mol. Cell. Biol. source

In the paper

“Ultimately, inhibition of cyclin–CDK complexes by p21 and p16 results in the persistent activation of RB, that represses cell cycle progression by sequestering E2F family members.”

In the paper

“In senescent cells, p21 enforces G1 arrest by inhibitory binding to cyclin E–CDK2 and cyclin A–CDK2 complexes, thus ensuring that RB remains hypo-phosphorylated and active.”

In the paper

“In senescence, p16 induction could represent the major switch to RB engagement in its active form and to irreversible cell cycle arrest (discussed further below).”

In the paper

“Due to the critical regulatory role of these cell cycle factors, senescence signaling typically acts by decreasing cyclin–CDK activity or increasing CDK inhibitor levels.”

What the sources say

• Not checked yetcites [33] Dyson, 1998, The regulation of E2F by pRB-family proteins, Genes Dev. source
• Not checked yetcites [34] Sherr, 1999, CDK inhibitors: Positive and negative regulators of G1-phase progression, Genes Dev. source

In the paper

“Senescent cells may also stop in G2 to block mitosis in the presence of DNA damage [32] (Figure 1).”

What the sources say

• Not checked yetcites [32] Gire, 2015, Senescence from G2 arrest, revisited, Cell Cycle source

In the paper

“As primary fibroblasts divide in culture, telomere shortening activates p53 [40].”

What the sources say

• Not checked yetcites [40] Bond, 1996, Evidence That Transcriptional Activation by P53 Plays a Direct Role in the Induction of Cellular Senescence, Oncogene

In the paper

“Among the p53 target genes, p21 is induced rapidly upon telomere damage.”

In the paper

“As cyclin B1–CDK1 complexes inhibit APC/C in complex with its co-activator CDH1 (APC/C CDH1) [64], the absence of mitotic CDK activity promotes the premature activation of APC/C CDH1 that targets cyclin B1 and other mitotic regulators for degradation.”

What the sources say

• Not checked yetcites [64] Zachariae, 1998, Control of Cyclin Ubiquitination by CDK-Regulated Binding of Hct1 to the Anaphase Promoting Complex, Science source

In the paper

“At the same time, p16 induction is robust in response to oncogenic stimuli, even in cells that undergo replicative senescence with low p16 levels [52].”

What the sources say

• Not checked yetcites [52] Bartkova, 2011, Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16 ink4a, Cell Cycle source

In the paper

“Moreover, p21 is not induced by p53 or DNA damage but is regulated by the transforming growth factor (TGF)-β/SMAD and PI3K/Forkhead box O (FOXO) signaling pathways [27].”

What the sources say

• Not checked yetcites [27] Maraver, 2013, Programmed Cell Senescence during Mammalian Embryonic Development, Cell source

In the paper

“When acute telomere damage is caused by inhibition of the telomere binding protein, TRF2, p16 protein levels increase in senescent cells [49].”

What the sources say

• Not checked yetcites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source

In the paper

“In human fibroblasts that carry p16 gene inactivating mutations, senescence is bypassed [53].”

What the sources say

• Not checked yetcites [53] Brookes, 2002, INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence, EMBO J. source

In the paper

“Although traditionally described as an irreversible form of G1 arrest, cellular senescence can also start during the G2 phase in response to telomere damage [57], DNA damage [58], or oncogene activation [59].”

What the sources say

• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source
• Not checked yetcites [58] Krenning, 2014, Transient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence, Mol. Cell source
• Not checked yetcites [59] Johmura, 2014, Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction, Mol. Cell source

In the paper

“Unlike, G1 arrest, cell cycle exit in G2 occurs rapidly, within few hours after damage [58].”

What the sources say

• Not checked yetcites [58] Krenning, 2014, Transient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence, Mol. Cell source

In the paper

“Surprisingly, developmental senescence is not required for embryogenesis because embryos lacking p21 show minimal or no developmental defects [56].”

What the sources say

• Not checked yetcites [56] Brugarolas, 1995, Radiation-Induced Cell Cycle Arrest Compromised by P21 Deficiency, Nature source

In the paper

“Other mechanisms, such as apoptosis, may partially compensate for the loss of developmental senescence in such embryos [27,28].”

What the sources say

• Not checked yetcites [27] Maraver, 2013, Programmed Cell Senescence during Mammalian Embryonic Development, Cell source
• Not checked yetcites [28] Storer, 2013, Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning, Cell source

In the paper

“Senescence is classically viewed as a stress response but can also occur in mouse and human embryos [27,28].”

What the sources say

• Not checked yetcites [27] Maraver, 2013, Programmed Cell Senescence during Mammalian Embryonic Development, Cell source
• Not checked yetcites [28] Storer, 2013, Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning, Cell source

In the paper

“Over time, telomere damage signaling can promote the progression of transiently arrested cells to full senescence through p16 upregulation [48].”

What the sources say

• Not checked yetcites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. source

In the paper

“Their unscheduled degradation is believed to result in cell cycle exit in G2 [32].”

What the sources say

• Not checked yetcites [32] Gire, 2015, Senescence from G2 arrest, revisited, Cell Cycle source

In the paper

“Moreover, p21 can indirectly activate RB family proteins that transcriptionally repress mitotic regulators, therefore stopping G2/M progression.”

In the paper

“After expression of an activated oncogene such as RASV12, p21 and p16 accumulate concomitantly and rapidly in human fibroblasts, resulting in oncogene-induced senescence (OIS) [51].”

What the sources say

• Not checked yetcites [51] Serrano, 1997, Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a, Cell source

In the paper

“This indicates that p21 has a primary role in the initial steps of the cell cycle arrest.”

In the paper

“Telomere damage and oncogenic stress induce p16 through different mechanisms.”

In the paper

“This initial arrest is reversible because senescent cells that express low levels of p16 can re-enter the cell cycle upon p53 inactivation [47,48].”

What the sources say

• Not checked yetcites [47] Gire, 1998, Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-p53 Antibodies, Mol. Cell. Biol. source
• Not checked yetcites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. source

In the paper

“Benign melanocytic lesions, which are melanoma precursors in humans, express high p16 and are an in vivo example of OIS [19,55].”

What the sources say

• Not checked yetcites [19] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source
• Not checked yetcites [55] Cheong, 2006, Cellular senescence in naevi and immortalisation in melanoma: A role for p16?, Br. J. Cancer source

In the paper

“In senescent embryonic cells, p21, but not p16, enforces cell cycle arrest, together with p15 that is a p16-related CDK inhibitor.”

What the sources say

• Not checked yetcites [27] Maraver, 2013, Programmed Cell Senescence during Mammalian Embryonic Development, Cell source

In the paper

“Therefore, G2 and G1 (for cells with 4N DNA content after mitosis by-pass) might be the phases at which senescent cells exit the cell cycle upon acute and robust DNA damage that induces a rapid cell response, typically within 24 h [58,59].”

What the sources say

• Not checked yetcites [58] Krenning, 2014, Transient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence, Mol. Cell source
• Not checked yetcites [59] Johmura, 2014, Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction, Mol. Cell source

In the paper

“For example, mouse embryonic fibroblasts (MEFs) lacking p53 [72] but not Ink4a (p16) or RB [73,74,75] escape Ras-induced senescence.”

What the sources say

• Not checked yetcites [72] Kamijo, 1997, Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19 ARF, Cell source
• Not checked yetcites [73] Sage, 2000, Targeted disruption of the three Rb-related genes leads to loss of G1 control and immortalization, Genes Dev. source
• Not checked yetcites [74] Krimpenfort, 2001, Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice, Nature source
• Not checked yetcites [75] Sharpless, 2001, Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis, Nature source

In the paper

“Therefore, senescent cells invariably display high levels of at least one of these key cell cycle inhibitors, a molecular hallmark of cellular senescence.”

In the paper

“This multiplicity of senescence markers represents different senescence stages.”

In the paper

“The EZH2 histone methyltransferase (a component of the PRC2 complex) catalyzes trimethylation of lysine 27 on histone 3 (H3K27me3), a repressive mark, on chromatin to silence the CDKN2A locus.”

In the paper

“Nevertheless, some effectors are common to the majority of known senescent states.”

In the paper

“Upon telomere erosion, senescing human fibroblasts show a prolonged G2 arrest, indicative of some mitotic entry delay [57].”

What the sources say

• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“In senescent cells, p53 transcriptional activity is increased through DNA damage response (DDR)-dependent signals mainly driven by unresolved DNA damage signaling due to telomere erosion and oncogene hyperproliferation [10,11,69,70,71].”

What the sources say

• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source
• Not checked yetcites [69] Bartkova, 2006, Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints, Nature source
• Not checked yetcites [70] Fumagalli, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature source
• Not checked yetcites [71] Takai, 2003, DNA Damage Foci at Dysfunctional Telomeres, Curr. Biol. source

In the paper

“Conversely, loss of functional p16 [53] but not of p53 [51,76] enables human fibroblasts to avoid Ras-induced senescence.”

What the sources say

• Not checked yetcites [53] Brookes, 2002, INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence, EMBO J. source
• Not checked yetcites [51] Serrano, 1997, Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a, Cell source
• Not checked yetcites [76] Wei, 2001, Role of p14 ARF in Replicative and Induced Senescence of Human Fibroblasts, Mol. Cell. Biol. source

In the paper

“Altogether, different senescence stimuli engage different signaling pathways that ultimately converge to influence the levels of senescent state regulators.”

In the paper

“Cell cycle exit during OIS is strictly dependent on the activation of RB that acts downstream of p16.”

In the paper

“In proliferative cells, polycomb repressive complexes (PRC1 and PRC2) are recruited by the long noncoding RNA ANRIL to the CDKN2A locus [79].”

What the sources say

• Not checked yetcites [79] Yap, 2010, Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a, Mol. Cell source

In the paper

“For example, loss of RB can trigger p53 upregulation via ARF or DNA damage signaling, thereby providing a safeguard to prevent senescence escape and malignant transformation [50,68].”

What the sources say

• Not checked yetcites [50] Bond, 1999, Control of Replicative Life Span in Human Cells: Barriers to Clonal Expansion Intermediate Between M1 Senescence and M2 Crisis, Mol. Cell. Biol. source
• Not checked yetcites [68] Chicas, 2010, Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence, Cancer Cell source

In the paper

“Cells can become senescent in response to different damaging stimuli. Most common inducers include DNA damage (e.g., telomere shortening or dysfunction, oncogene activation, oxidative damage, radiation); metabolic stresses (e.g., mitochondrial dysfunction, redox states changes), inflammatory cytokines/chemokines and damage signals (e.g., protein misfolding, autophagy disruption).”

In the paper

“Therefore, p53 and p16 may not be universal OIS mediators in human cells.”

In the paper

“This epigenetic mark is recognized and enforced by PRC1 that contains B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), chromobox protein homologue 7 (CBX7), and chromobox protein homologue 8 (CBX8).”

In the paper

“Namely, the p53/ARF and RB/p16 tumor suppressor pathways act in a cooperative and interconnected way to block the cell cycle and implement the senescence programs.”

In the paper

“Most notably mitotic by-pass, which results from insufficient levels of mitotic proteins, is sufficient and necessary for OIS both in vitro and in vivo [59].”

What the sources say

• Not checked yetcites [59] Johmura, 2014, Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction, Mol. Cell source

In the paper

“Unlike acute senescence, replicative senescence results from chronic, low-level macromolecular damage caused by telomere erosion and increased reactive oxygen species (ROS) levels (due to mitochondrial dysfunction and/or environmental insults).”

In the paper

“When this mechanism fails, cells that are long-term arrested in G2 can enter a permanent G1-like state without going through mitosis (mitosis by-pass), thereby generating tetraploid cells [59] (Figure 1).”

What the sources say

• Not checked yetcites [59] Johmura, 2014, Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction, Mol. Cell source

In the paper

“Due to the multiplicity of stress signals and effector pathways involved in its execution, cellular senescence is associated with various phenotypes the characteristics of which depend on the signals that induced senescence, the originating cell type, the time elapsed since senescence initiation, and the site where senescent cells are located.”

In the paper

“At these foci, γH2AX rapidly concentrates and anchors DNA repair proteins, such as 53BP1, MDC1, and NBS1, in the vicinity of telomeric lesions.”

In the paper

“Shelterin allows the efficient suppression of non-homologous end joining (NHEJ) and ATM activation at chromosome ends [89].”

What the sources say

• Not checked yetcites [89] Ruis, 2021, The end protection problem—An unexpected twist in the tail, Genes Dev. source

In the paper

“Indeed, random damage to telomeres through oxidative damage [91], exonucleolytic processing events, nucleases [92], secondary structures in telomeric DNA [93], and sporadic loss of large telomeric stretches [94] also can accelerate telomere shortening and dysfunction.”

What the sources say

• Not checked yetcites [91] 2002, Oxidative stress shortens telomeres, Trends Biochem. Sci. source
• Not checked yetcites [92] Lydall, 2003, Hiding at the ends of yeast chromosomes: Telomeres, nucleases and checkpoint pathways, J. Cell Sci. source
• Not checked yetcites [93] Ding, 2004, Regulation of Murine Telomere Length by Rtel: An Essential Gene Encoding a Helicase-like Protein, Cell source

In the paper

“In this situation, foci of phosphorylated histone H2AX (γH2AX), which mark the presence of DNA breaks, accumulate at telomeres in human senescent fibroblasts [10,11,12].”

What the sources say

• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source
• Not checked yetcites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source

In the paper

“Therefore, too short telomeres might retain sufficient telomere length and TRF2 to suppress chromosome end-to-end fusions via the NHEJ pathway but not to efficiently protect telomeres against ATM activation.”

In the paper

“γH2AX focus formation correlates with the activation of the DNA damage effector kinases ATM, CHK1, and CHK2 [10,11,12].”

What the sources say

• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source
• Not checked yetcites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source

In the paper

“However, in senescent human cells, short telomeres do not recapitulate the intermediate state phenotype predicted by this model (i.e., mild ATM activation without evidence of significant CHK2 and p53 activation) [10,11,12,57].”

What the sources say

• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source
• Not checked yetcites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source
• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“Telomeres shorten at each cell replication because of the end-replication problem and post replicative end-processing [89,90].”

What the sources say

• Not checked yetcites [89] Ruis, 2021, The end protection problem—An unexpected twist in the tail, Genes Dev. source
• Not checked yetcites [90] Harley, 1990, Telomeres shorten during ageing of human fibroblasts, Nature source

In the paper

“As t-loops require a G-overhang, loss of G-overhangs in senescent cells, possibly due to perturbations in end-protection, restricts t-loop formation [100].”

What the sources say

• Not checked yetcites [100] Stewart, 2003, Erosion of the telomeric single-strand overhang at replicative senescence, Nat. Genet. source

In the paper

“Nevertheless, it is unlikely that the inability to properly repair DNA breaks in telomeres is the only mechanism by which senescence is induced following exposure to exogenous DNA damaging agents.”

In the paper

“Similarly, when cells are exposed to oxidative or DNA damaging agents, if the damage occurs in telomeric regions, TRF2 inhibits its repair and contributes to an unresolved DDR, which helps to stabilize the senescence arrest [115].”

What the sources say

• Not checked yetcites [115] Fumagalli, 2012, Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation, Nat. Cell Biol. source

In the paper

“Accumulation of γH2AX foci in senescent cells in culture and in cells derived from aged individuals can mark also non-repaired DNA breaks that are not necessarily the result of critically short telomeres [106].”

What the sources say

• Not checked yetcites [106] Sedelnikova, 2004, Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks, Nat. Cell Biol. source

In the paper

“Progression to mitosis in cells with residual damage or fused chromosomes contributes to the generation of micronuclei upon cytokinesis [105].”

What the sources say

• Not checked yetcites [105] Ivanov, 2013, Lysosome-mediated processing of chromatin in senescence, J. Cell Biol. source

In the paper

“For example, telomere dysfunction, assessed by the association of DDR proteins with telomeres, increases with age in vivo in baboon skin fibroblasts [107,108] and in mouse liver and gut [109].”

What the sources say

• Not checked yetcites [107] Herbig, 2006, Cellular Senescence in Aging Primates, Science source
• Not checked yetcites [108] Jeyapalan, 2007, Accumulation of senescent cells in mitotic tissue of aging primates, Mech. Ageing Dev. source
• Not checked yetcites [109] Hewitt, 2012, Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence, Nat. Commun. source

In the paper

“These age-associated foci occur despite the presence of long telomeres and active telomerase in mice.”

What the sources say

• Not checked yetcites [109] Hewitt, 2012, Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence, Nat. Commun. source

In the paper

“Conversely, telomerase expression in human fibroblasts does not protect them against senescence induced by oxidative damage [112] and OIS [113].”

What the sources say

• Not checked yetcites [112] Chainiaux, 2002, Stress-induced premature senescence in BJ and hTERT-BJ1 human foreskin fibroblasts, FEBS Lett. source
• Not checked yetcites [113] Wei, 1999, Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts, Cancer Res.

In the paper

“In fact, lesions in or next to telomeres are refractory to repair as a result of TRF2 presence.”

What the sources say

• Not checked yetcites [109] Hewitt, 2012, Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence, Nat. Commun. source
• Not checked yetcites [115] Fumagalli, 2012, Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation, Nat. Cell Biol. source

In the paper

“Culture of primary mouse and human fibroblasts at low physiological oxygen levels prevents senescence activation after long culturing (increasing passage number) or upon expression of activated Ras [54,111].”

What the sources say

• Not checked yetcites [54] Benanti, 2004, Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence, Mol. Cell. Biol. source
• Not checked yetcites [111] Parrinello, 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, Nat. Cell Biol. source

In the paper

“Consequently, the cell cycle stalls in G2 to provide time for the re-establishment of the folded structure after replication [57].”

What the sources say

• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“Inherited dysfunctional telomeres and additional DNA breaks following mitosis will cause G1 arrest in the resulting daughter cells (Figure 1).”

In the paper

“However, high telomerase activity prevents the activation of DNA damage signals originating from stalled replication forks inside telomeres, thus allowing OIS bypass [114].”

What the sources say

• Not checked yetcites [114] Suram, 2012, Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions: Telomere Dysfunction Limits Cancer Progression in Humans, EMBO J. source

In the paper

“DNA damage signaling is also involved in the initiation of stress-induced premature senescence in response to acute cellular stresses, such as oxidative damage generated by ROS [117] and oncogene activation [69,70].”

What the sources say

• Not checked yetcites [117] Colavitti, 2005, Reactive Oxygen Species as Mediators of Cellular Senescence, IUBMB Life source
• Not checked yetcites [69] Bartkova, 2006, Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints, Nature source
• Not checked yetcites [70] Fumagalli, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature source

In the paper

“The accumulation of persistent and unresolved telomeric damage might be explained by the cell inability to efficiently repair damaged telomeres [109,115].”

What the sources say

• Not checked yetcites [109] Hewitt, 2012, Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence, Nat. Commun. source
• Not checked yetcites [115] Fumagalli, 2012, Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation, Nat. Cell Biol. source

In the paper

“As telomeres shorten, the frequency of t-loop occurrence would decrease due to reduced occupancy by TRF2 required to form a functional t-loop structure after DNA replication.”

In the paper

“Therefore, cells with a low number of DNA breaks can enter mitosis [103,104].”

What the sources say

• Not checked yetcites [103] Deckbar, 2007, Chromosome breakage after G2 checkpoint release, J. Cell Biol. source
• Not checked yetcites [104] Krempler, 2007, An Imperfect G2M Checkpoint Contributes to Chromosome Instability Following Irradiation of S and G2Phase Cells, Cell Cycle source

In the paper

“Alternatively, cells approaching senescence may proceed to mitosis despite the presence of residual (4 to 5) γH2AX-marked unstable telomere structures [102].”

What the sources say

• Not checked yetcites [102] Kaul, 2012, Five dysfunctional telomeres predict onset of senescence in human cells, EMBO Rep. source

In the paper

“In addition to aberrant DNA replication, unrepaired telomeres contribute to DDR signaling in OIS, without significant telomere shortening.”

In the paper

“In mouse models, deficiency of one or both proteins encoded by the CDKN2A locus results in tumor-prone animals [123].”

What the sources say

• Not checked yetcites [123] Kim, 2006, The Regulation of INK4/ARF in Cancer and Aging, Cell source

In the paper

“Conversely, efficient ARF induction mainly reflects a transcription-based mechanism under continuous oncogenic activation [129].”

What the sources say

• Not checked yetcites [129] Evangelou, 2013, The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis, Cell Death Differ. source

In the paper

“ARF acts mainly by binding to MDM2, a p53-specific E3 ubiquitin ligase, to prevent its effect on p53 inactivation, thereby stabilizing and enhancing p53 activity.”

In the paper

“Indeed, its locus is more commonly deleted or silenced than mutated in melanoma, the more malignant later stage of disease [19,55].”

What the sources say

• Not checked yetcites [19] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source
• Not checked yetcites [55] Cheong, 2006, Cellular senescence in naevi and immortalisation in melanoma: A role for p16?, Br. J. Cancer source

In the paper

“For example, N-RAS- or B-RAF-activating mutations are commonly found in benign melanocytic nevi that show features of senescence, such as elevated p16 levels, but that do not express appreciable levels of ARF or p53 [19,55].”

What the sources say

• Not checked yetcites [19] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source
• Not checked yetcites [55] Cheong, 2006, Cellular senescence in naevi and immortalisation in melanoma: A role for p16?, Br. J. Cancer source

In the paper

“Activated oncogenes deregulate cell cycle entry by increasing the activities of CDKs that function as positive S phase regulators.”

In the paper

“Oncogene-induced replication stress and DNA breaks account for the early DDR activation mediated primarily by phosphorylation-dependent signaling [69].”

What the sources say

• Not checked yetcites [69] Bartkova, 2006, Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints, Nature source

In the paper

“Indeed, such telomeres are not visibly shorter than functional telomeres [114] in human melanocytic nevi with frequent BRAF mutations, a typical OIS feature in vivo [19].”

What the sources say

• Not checked yetcites [114] Suram, 2012, Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions: Telomere Dysfunction Limits Cancer Progression in Humans, EMBO J. source
• Not checked yetcites [19] Michaloglou, 2005, BRAFE600-associated senescence-like cell cycle arrest of human naevi, Nature source