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Cited by 823Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

Telomeres and telomerase in cancer

Open access
Artandi, S. E., DePinho, R. A.·2010·Carcinogenesis
DOI 10.1093/carcin/bgp268PMC PMC3003493
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Abstract

Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host. Cancer genomes are highly rearranged and are characterized by complex translocations and regional copy number alterations that target loci harboring cancer-relevant genes. Efforts to uncover the underlying mechanisms driving genome instability in cancer have revealed a prominent role for telomeres. Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability. Indeed, telomere erosion has been documented in aging tissues and hyperproliferative disease states-conditions strongly associated with increased cancer risk. Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses. In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.

Integrity signals

Registry

Crossref · 10.1093/carcin/bgp268

Cites

77 of 77 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Findingcitation

    By one year of age, all mice in this cohort had neoplastic lesions of the colonic epithelium.

    “In fact, by one year of age, all mice in this cohort harbored neoplastic lesions of the colonic epithelium.”
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  • Findingreasoning

    This survival and continued cycling led to accumulation of cells with abnormal cytogenetic profiles consistent with ongoing telomere dysfunction and chromosomal fusion-breakage cycles.

    “However, this cell survival and continued cycling resulted in the accumulation of cells with strikingly abnormal cytogenetic profiles consistent with ongoing telomere dysfunction and its associated chromosomal fusionbreakage cycles upon cell division.”
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  • Findingcitation

    Unlike p53+/- mice with intact telomeres, G5/G6 TERC-/- p53+/- mice developed epithelial cancers, particularly skin, breast and gastrointestinal.

    “In contrast to the typical tumor spectrum of p53þ/À mice with intact telomeres, G5/G6 TERCÀ/À p53þ/À mice developed epithelial cancers, particularly those of the skin, breast and gastrointestinal tract.”
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  • Premisecitation

    TIN2 interacts with the TPP1-POT1 subcomplex that binds the single-stranded overhang.

    “TRF1-interacting nuclear factor 2 also interacts with the subcomplex of shelterin that binds the single-stranded overhang-TPP1 and POT1, two oligonucleotide/ oligosaccharide binding (OB)-fold containing proteins (13)(14)(15).”
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  • Premisecitation

    Overexpression of POT1 shortens telomeres by inhibiting telomerase action at the telomere.

    “Overexpression of POT1 leads to telomere shortening by inhibiting telomerase action at the telomere (20).”
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    Findingcitation

    In G5/G6 TERC-/- p53-/- mice, p53 loss restored cellularity and proliferation and reduced apoptosis across many tissues, consistent with deactivation of a p53-dependent DNA damage response.

    “In G5/ G6 TERCÀ/À p53À/À mice, we showed dramatic and widespread restoration of cellularity and cellular proliferation and reduction in apoptosis across many tissues-findings consistent with deactivation of a p53-dependent DNA damage response (70).”
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    Findingown data

    G5/G6 TERC-/- p53+/- epithelial tumors lost the wild-type p53 allele and frequently formed anaphase bridges consistent with dicentric chromosomes.

    “The G5/G6 TERCÀ/À p53þ/À epithelial tumors sustained loss of the wild-type p53 allele and showed frequent anaphase bridge formation consistent with the formation of dicentric chromosomes.”
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    Findingcitation

    G5/G6 TERC-/- p53-/- or p53+/- mice showed significant acceleration of tumor formation and altered tumor spectrum.

    “G5/G6 TERCÀ/À p53À/À (or p53þ/À) mice showed significant acceleration of the rate of tumor formation and altered the spectrum of tumor types (104).”
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    Findingown data

    Spectral karyotype analysis showed chromosomal end fusions and numerous non-reciprocal translocations between non-homologous chromosomes in these tumors, not seen in p53-deficient mice with long telomeres.

    “On the cytogenetic level, spectral karyotype analysis showed chromosomal end fusions and numerous translocations between non-homologous chromosomes.These translocations were of the non-reciprocal type and were not seen in cancers from p53-deficient mice with long telomeres.”
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    Premisecitation

    Overexpression of TERT prevents senescence and crisis in these fibroblasts.

    “Senescence and crisis in these fibroblasts are effectively averted by overexpresssion of telomerase reverse transcriptase (TERT), the catalytic protein subunit of telomerase, an enzyme complex that synthesizes telomere repeats (28,29).”
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    Premisecitation

    Shortened telomeres activate a senescence program, and this growth arrest can be overcome by inactivating p53 and Rb.

    “These shortened telomeres activate a 'senescence' program, and this growth arrest phenotype can be neutralized through inactivation of p53 and Rb (the Retinoblastoma tumor suppressor protein) (25,26).”
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    Premisecitation

    TRF1 can regulate telomere length and also helps DNA replication through telomere repeats.

    “TRF1 can serve to modulate telomere length, but it also serves to facilitate DNA replication through the telomere repeats, which acts as fragile DNA sites (5)(6)(7).”
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    Premisecitation

    TCAB1 (WDR79) is a WD40-repeat protein that binds dyskerin and the CAB box in scaRNAs.

    “TCAB1 (also known as WDR79) is a WD40-repeat containing protein that associates with dyskerin and binds the CAB box in scaRNAs (46,47).”
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    Premisecitation

    Telomeres shorten progressively as normal human fibroblasts divide in culture, but they are maintained in cancer cells.

    “A first critical clue of the mechanistic basis for this distinction came with the observation that telomeres shorten progressively during division of normal human fibroblasts in culture, yet are maintained in cancer cells (24).”
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    Premisecitation

    TRF2 is essential for protecting telomere ends and can promote t-loop formation.

    “TRF2 is critical for telomere end protection and can facilitate formation of the t-loop conformation.”
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    Premisecitation

    TRF1 and TRF2 bind TIN2, which nucleates a six-protein shelterin complex that also contains TRF2-interacting protein, POT1, and TPP1.

    “TRF1 and TRF2 each interact with a common factor TRF1interacting nuclear factor (TIN2) (8), which nucleates a six-member complex, termed shelterin, that also includes telomeric repeat binding factor 2-interacting protein, protection of telomeres 1 (POT1) and TPP1 (9).”
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    Interpretationnone given
    § Telomeres and telomerase in cancer

    Telomere dysfunction can lead either to degenerative aging or to cancer, and which outcome occurs depends on how intact the DNA damage checkpoint responses are.

    “Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses.”
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    Premisecitation

    Loss of POT1 impairs telomere capping, showing that POT1 and TPP1 protect the single-stranded portion of telomeres.

    “POT1 and TPP1 serve a role in protecting the single-stranded portion of the telomere because loss of POT1 impairs telomere capping (16)(17)(18)(19).”
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    Premisecitation

    Vertebrate telomeres contain TTAGGG repeats, a long double-stranded region, and a single-stranded 3' overhang of a few hundred nucleotides.

    “In vertebrates, telomeres are composed of the sequence TTAGGG and include a double-stranded tract of repeats many kilobases long and an obligate single-stranded 3# overhang, measuring a few hundred nucleotides (1).”
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    Premisecitation

    With further divisions, human fibroblasts continue to lose telomeres, capping fails, chromosomal instability becomes widespread, and apoptosis occurs, a state called crisis.

    “However, as these human fibroblasts undergo additional cell divisions, telomere erosion continues and the loss of telomere capping function produces rampant chromosomal instability and widespread apoptosis, a cellular state termed crisis (27).”
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    Premisecitation

    When TRF2 is disrupted, the protective capped structure is lost, the 3' overhang is processed, and chromosome ends become ligated.

    “Disruption of TRF2 through overexpression of a dominant-negative form or through deletion in TRF2-knockout mouse embryo fibroblasts leads to loss of the protective capped structure, characterized by processing of the 3# overhang and ligation of chromosome ends (3,4).”
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    Premisecitation

    Mammalian TRF2-interacting protein is recruited to telomeres through TRF2 and may help repress non-homologous end joining.

    “Unlike yeast Rap1p, mammalian telomeric repeat binding factor 2-interacting protein does not bind telomeric DNA directly but is instead recruited to telomeres through its interaction with TRF2, where it may act to aid in repression of non-homologous end joining (11,12).”
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    Premisecitation

    Mouse and human TERC have an H/ACA sequence motif at the 3' end that defines a class of non-coding RNAs.

    “In this region, mouse and human TERC possess an H/ACA sequence motif that defines a specific class of non-coding RNAs (35,36).”
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    Premisecitation

    In late-generation TERC-/- mice, p53 protein is stabilized, and loss of p53 significantly reduces the cell cycle arrest and cell death phenotypes.

    “In late-generation TERCÀ/À mice, p53 protein is stabilized and loss of p53 significantly attenuates the cell cycle arrest and cell death phenotypes in TERCÀ/À tissues (70).”
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    Premisecitation

    Each telomerase component is dispensable for life, and telomerase-knockout mice are remarkably normal.

    “Surprisingly, each telomerase component was found to be dispensable for life and these telomerase-knockout mice were remarkably normal (60).”
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    Premisecitation

    In the APC min model, adding telomere dysfunction increases early neoplastic lesions, probably because chromosome instability causes loss of the remaining wild-type APC allele.

    “In this APC min model, the addition of telomere dysfunction resulted in an increase in early neoplastic lesions probably due to chromosome instability resulting in increased loss of the remaining wild-type APC allele.”
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    Premisecitation

    G4 TERC-/- APC min mice show profound suppression of more advanced adenomatous lesions, associated with intratumoral growth arrest and apoptosis.

    “However, these G4 TERCÀ/À APC min mice exhibited a profound suppression of more advanced adenomatous lesions in association with significant intratumoral growth arrest and apoptosis (89).”
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    Interpretationcitation

    The severe degenerative tissue defects in late-generation telomerase-knockout mice are linked to impaired proliferation and increased apoptosis in cycling progenitor cells and to a self-renewal defect in tissue stem cells.

    “The severe degenerative tissue defects in the late-generation telomerase-knockout mice appear linked to impaired proliferation and increased apoptosis in cycling progenitor cells and to a selfrenewal defect in tissue stem cells.”
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    Premisecitation

    Early studies found strong suppression of TERT expression and telomerase activity in human somatic tissues, but robust expression in germ cells and cancer cells.

    “Early studies cataloging TERT expression and telomerase activity reported potent suppression in human somatic tissues, yet robust expression and activity in germ cells and cancer cells (48).”
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  • May combine two claims.

    Interpretationreasoning

    Factors affecting genome integrity and/or modulating p53-dependent responses will impact the aging phenotype, as supported by the attenuation of degenerative aging in telomerase-deficient mice null for p53.

    “This model implies that factors affecting genome integrity (such as telomeres, reactive oxygen species and DNA repair) and/or modulating p53-dependent responses (such as sirtuins) will impact on the aging phenotype, a view that is clearly supported by the dramatic attenuation of degenerative aging in telomerase-deficient mice null for p53.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In G4/G5 TERC-/- Ink4a/Arf-/- mice, telomere dysfunction reduces tumor incidence and increases latency without changing the tumor spectrum.

    “however, in the setting of telomere dysfunction, G4/G5 TERCÀ/À Ink4a/ArfÀ/À mice show reduced tumor incidence and increased latency (87,88) and no change in the tumor spectrum.”
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    Premisecitation

    Late-generation telomerase-knockout mice show a premature aging syndrome with hair graying, shortened survival, and impaired responses to acute and chronic stress.

    “Late-generation telomerase-knockout mice exhibit a premature aging syndrome characterized by hair graying, shortened survival and impaired responses to acute and chronic stress (63,77).”
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    Premisecitation

    Reactive oxygen species can induce DNA damage and accelerate telomere erosion, potentially amplifying checkpoint responses.

    “Indeed, it is worth noting that reactive oxygen species, which can induce DNA damage, are capable of accelerating Telomeres and telomerase in cancer telomere erosion that may further amplify checkpoint responses (79).”
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    Premisecitation

    G5-G6 TERC-/- mice become infertile, show high apoptosis in testis, germ cell depletion, impaired bone marrow function, and reduced lymphocyte proliferation.

    “G5-G6 TERC mice became infertile, showed high rates of apoptosis in testis and germ cell depletion, exhibited impaired bone marrow function and diminished proliferation of lymphocytes (61).”
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    Premisecitation

    Telomerase is reactivated when human fibroblasts are reprogrammed to induced pluripotent stem cells and is strongly expressed in human embryonic stem cells.

    “Telomerase is reactivated during the reprogramming of human fibroblasts to induced pluripotent stem cells and is expressed robustly in human embryonic stem cells (54).”
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    Premisecitation

    In most cases, enforced expression of exogenous TERT was required for transformation of human cells, with exceptions such as keratinocytes transformed by IκBα and activated H-RAS.

    “In the vast majority of cases, enforced expression of exogenous TERT was required for transformation, although there are some exceptions such as human keratinocytes wherein Inhibitor NFjB a (IjBa) and activated H-RAS can drive transformation to squamous cell carcinoma (98).”
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    Interpretationreasoning

    Human cell data support the view that telomerase reactivation is required for malignant transformation; if TERT is not supplied exogenously, endogenous telomerase is expressed through selection, direct regulation by cancer genes, or transformation of a rare telomerase-expressing progenitor population.

    “Similarly, the data in human cells also strongly support the view that telomerase reactivation is required for malignant transformation and, if TERT is not exogenously supplied, endogenous telomerase is expressed through selection, through direct regulation by the cancer genes employed or through transformation of a rare progenitor cell population expressing telomerase in the culture of human cell”
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    • Rests on an assumption: Potent oncogene combinations are highly inefficient at malignantly transforming cultured human cells.

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    Premisecitation

    In a transgenic breast cancer model driven by Polyoma Middle T antigen, telomere dysfunction impaired tumor latency and penetrance and reduced metastatic potential.

    “In a transgenic breast cancer model driven by Polyoma Middle T antigen, telomere dysfunction significantly impaired not only tumor latency and penetrance but also reduced metastatic potential (90).”
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    Interpretationreasoning

    Senescence and apoptosis responses induced by telomere dysfunction and p53 activation contribute to tumor suppression, with their relative roles probably varying by cell type and genetic context.

    “Together, these findings indicate that senescence and apoptosis responses induced by telomere dysfunction and p53 activation contribute to tumor suppression and that their relative roles probably vary based on cell type and the genetic context of the incipient cancer.”
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    Interpretationown data

    Telomere shortening and dysfunction unchecked by p53 deactivation accelerates rather than limits carcinogenesis and promotes epithelial tumor formation.

    “Thus, telomere shortening and dysfunction that proceeds unchecked in the setting of deactivated p53 serves to accelerate, rather than limit, carcinogenesis and promotes tumor formation in epithelial compartments.”
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    Interpretationcitation

    Either progressive telomere shortening or acute telomere uncapping can lead to non-reciprocal translocations through a fusion-breakage mechanism.

    “Thus, either progressive telomere shortening or acute telomere uncapping can lead to non-reciprocal translocations through a fusionbreakage mechanism.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Tumors that emerged in these models showed ALT activation, p53 mutation and/or diminished capacity to become fully malignant.

    “Those tumors that did emerge showed activation of alternative lengthening of telomeres (ALT), mutation of p53 and/or a diminished capacity to achieve a fully malignant state (88,100).”
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    Premisecitation

    p53-mutant mice are cancer prone but their predilection for mesenchymal and lymphoid malignancies rather than epithelial cancers does not match the tumor types most commonly possessing p53 mutations in humans.

    “while p53-mutant mice are cancer prone, we noted that their predilection for mesenchymal and lymphoid malignancies, rather than epithelial cancers, did not represent the tumor types most commonly possessing p53 mutations in humans (101,102).”
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    Interpretationcitation

    TERT acts as a developmental regulator and modulates the Wnt signaling pathway.

    “These observations indicated that TERT possesses properties of a developmental regulator and indeed TERT exerts these potent developmental effects as a modulator in the Wnt signaling pathway (149).”
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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The hypothesis that telomere-based crisis and deactivation of DNA damage signaling are a major mechanism driving epithelial carcinogenesis in humans, particularly the aged, is consistent with multiple observations including age-related telomere shortening in epithelial compartments, short telomeres in established tumors, early massive genome instability followed by quelling, and anaphase bridging.

    “Our hypothesis that telomere-based crisis and deactivation of DNA damage signaling are a major mechanism driving epithelial carcinogenesis in humans, particularly the aged, is consistent with multiple observations including (i) telomere shortening in epithelial compartments with advancing age, (ii) short telomeres in established tumors indicating a period of telomere erosion at some point in tumor”
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    Interpretationcitation

    TERT's enhancement of Wnt signaling explains its activation of bulge stem cells, since β-catenin overexpression in mouse skin causes a similar stem cell activation phenotype.

    “The ability of TERT to enhance Wnt signaling explains how TERT activates bulge stem cells since overexpression of b-catenin in mouse skin causes a very similar stem cell-activation phenotype (150-152).”
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    Interpretationcitation

    TERT may amplify small non-coding RNAs and exert other activities through this mechanism.

    “These findings suggest that TERT may amplify small non-coding RNAs and exert other activities through this mechanism (153).”
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    Premisecitation

    In human breast cancer, chromosomal instability rates peaked at ductal carcinoma in situ, with anaphase bridges in pre-invasive stages during dramatic telomere shortening.

    “In human breast cancer, rates of chromosomal instability peaked at the ductal carcinoma in situ stage.As in the case of colon cancer, anaphase bridges were seen in pre-invasive stages and this evidence for chromosomal instability occurred during a period a dramatic telomere shortening (126).”
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    Premisecitation

    Telomerase is upregulated at ductal carcinoma in situ, consistent with telomere stabilization reducing chromosomal changes at invasive and metastatic stages.

    “Ductal carcinoma in situ is the stage at which telomerase is upregulated, which is consistent with the idea that telomere stabilization then reduces the rate of chromosomal changes at the invasive and metastatic stages (129).”
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    Premisecitation

    Overexpression experiments in transgenic mice and human cells have shown TERT has activities in cellular transformation, proliferation, stem cell biology, cell survival and chromatin regulation.

    “Overexpression experiments in transgenic mice and in human cells have shown that TERT exhibits activities in cellular transformation (136-138), proliferation (139), stem cell biology (140-142), cell survival (143,144) and chromatin regulation (145).”
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    Interpretationcitation

    Telomeres shorten during human epithelial cancer development, and short telomeres are evident at the earliest stages of human carcinogenesis.

    “These data indicate that telomeres shorten during epithelial cancer development in humans and that short telomeres are evident at the earliest stages of human carcinogenesis (127,128).”
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    Premisecitation

    Ulcerative colitis, a form of inflammatory bowel disease affecting the colon, is associated with telomere shortening, increased anaphase bridges and a high rate of colon cancer.

    “Ulcerative colitis is a form of inflammatory bowel disease that affects the colon and is associated with telomere shortening, increased anaphase bridges and a high rate of colon cancer (130).”
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    Premisecitation

    TERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease and ribonuclease P and can act as an RNA-dependent RNA polymerase.

    “In addition, TERT was shown to interact with RNA component of mitochondrial RNA processing endoribonuclease, the RNA component of ribonuclease P, and in this context TERT is able to act as an RNA-dependent RNA polymerase.”
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    Premisecitation

    TERT interacts with Brg-1, which binds β-catenin, and is recruited to Wnt target gene chromatin to enhance Wnt transcriptional output.

    “TERT interacts with the chromatin remodeling protein Brg-1, which binds b-catenin, the central transactivator in the Wnt pathway.TERT is recruited to Wnt target gene chromatin in cells stimulated by Wnts and serves to enhance the transcriptional output of the Wnt program in this context (148,149).”
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    Interpretationreasoning

    The human genome is widely altered through gene copy number changes, and telomere shortening during tumorigenesis can serve as a key mutator mechanism.

    “Together, these data indicate that the human genome is widely altered through changes in gene copy number and that telomere shortening during tumorigenesis can serve as a key mutator mechanism.”
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    Interpretationreasoning

    Conditions of enhanced proliferation and tissue damage in humans accelerate telomere shortening and destabilize chromosomes similarly to many human carcinomas.

    “Thus, conditions of enhanced proliferation and tissue damage in humans accelerate telomere shortening and destabilize chromosomes in a manner similar to that seen in many human carcinomas.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Chronic cellular damage leading to liver cirrhosis results in shortened telomeres, anaphase bridges and a dramatically increased risk of liver cancer.

    “Similarly, the chronic cellular damage that leads to liver cirrhosis results in shortened telomeres, anaphase bridges and a dramatically increased risk of liver cancer (131-134).”
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    • cites [132] source

      Not checked in the free run.

    • cites [133] source

      Not checked in the free run.

    • cites [134] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These TERT effects occurred in TERC-null mice and are independent of telomerase's canonical telomere repeat addition.

    “These effects of TERT occurred in mice null for TERC and therefore are independent of the canonical role of telomerase in adding telomere repeats (146).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anaphase bridges are low in adenomas but increase substantially at the adenoma-carcinoma transition and become significantly more abundant at pre-invasive and invasive colon cancer stages.

    “Anaphase bridges, a hallmark of dysfunctional telomeres, are low in adenomas but increase substantially at the adenoma-carcinoma transition.Anaphase bridges become significantly more abundant at the pre-invasive and invasive colon cancer stages (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomerase upregulation occurs at the dysplastic adenoma to carcinoma transition in human colon cancer, enhancing telomere maintenance and relative stability late in progression.

    “Similarly, upregulation of telomerase occurs at the dysplastic adenoma to carcinoma transition in human colon cancer, facilitating enhanced telomere maintenance and fostering relative stability late in tumor progression (120).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The gene target of these CNAs is unknown in the vast majority of loci, indicating many cancer genes remain undiscovered.

    “However, and more strikingly, the gene target of these CNAs is not known in the vast majority of loci indicating that a large number of cancer genes remain to be discovered.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: For most focal amplifications and deletions in human cancers, the relevant cancer genes are unknown.

  • May combine two claims.

    Interpretationreasoning

    Telomerase upregulation enhances cancer cell proliferation by maintaining telomere sequences, reducing intolerable chromosomal instability and preventing DNA damage checkpoint responses that would slow proliferation, induce senescence or trigger cell death.

    “In addition to stabilizing chromosomes, upregulation of telomerase clearly serves to enhance proliferation of cancer cells by maintaining telomere sequences, thereby reducing intolerable levels of chromosomal instability and preventing the DNA damage checkpoint responses that would slow proliferation, induce senescence or trigger cell death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This checkpoint defect permits survival with continued telomere shortening, leading to rampant chromosomal instability through fusion-bridge-breakage cycles.

    “This checkpoint defect allows survival in the face of continued telomere shortening, which now leads to rampant chromosomal instability through chromosome fusion-bridge-breakage cycles.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    TERT upregulation may enhance telomerase activity, stabilize short telomeres and support unlimited cell division.

    “Upregulation of TERT may yield enhanced telomerase activity and therefore stabilize short telomeres, supporting unlimited cell division.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Telomeres consist of double-stranded TTAGGG repeats that end in a single-stranded overhang.

    “Telomeres are TTAGGG double-stranded DNA repeats culminating in a single-stranded overhang.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Palm,W. et al. (2008) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The requirement for telomerase-mediated telomere maintenance in renewing tissues, together with telomere-independent TERT roles in progenitor cells, indicates that manipulating TERT may fulfill its promise in regenerative medicine.

    “The clear requirement for telomere maintenance by telomerase in renewing tissues, coupled with the emerging telomere-independent role for TERT in tissue progenitor cells, indicates that manipulating TERT may indeed fulfill its early promise in regenerative medicine.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    X-linked DC is caused by dyskerin mutations, leading to reduced TERC and telomerase activity.

    “In its X-linked form, DC is caused by mutations in dyskerin, which leads to reduced levels of TERC and telomerase activity (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Other DC features such as oral leukoplakia, nail dystrophy and pulmonary disease suggest dysfunctional telomeres broadly impair stem and progenitor cell function, agreeing with telomerase-knockout mice.

    “Other aspects of the disease including the oral leukoplakia, nail dystrophy and pulmonary disease suggest the possibility that dysfunctional telomeres in this disorder broadly impair function of stem cells and progenitor cells, findings in close agreement with those in telomerase-knockout mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    POT1 and TPP1 are OB-fold-containing proteins that associate with the single-stranded overhang.

    “POT1 and TPP1 are OB-fold containing proteins associated with the single stranded overhang.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Baumann,P. et al. (2001) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TIN2 is a central component of the shelterin complex that interacts with TRF1, TRF2 and TPP1.

    “RAP1 binds TRF2, and TIN2 is a central component of the complex interacting with TRF1, TRF2 and TPP1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kim,S.H. et al. (1999) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Intact telomere function is crucial for cell proliferation and survival, and telomere shortening can profoundly impact regenerative tissues, especially progenitor cell compartments.

    “Data from mouse and human systems indicate that intact telomere function is crucial for cell proliferation and survival and that telomere shortening can profoundly impact regenerative tissues, particularly in progenitor cell compartments.”
    Quote in the paperSubstantial claim
66 of 66

  • The paper relies on this without support.

    Telomeres protect chromosome ends and are vulnerable to progressive shortening during DNA replication, so tissue renewal increases the risk of chromosomal instability.

    “Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability.”

  • The paper relies on this without support.

    In most advanced cancers, telomerase is reactivated and maintains telomere length.

    “In most advanced cancers, telomerase is reactivated and serves to maintain telomere length”

  • The paper relies on this without support.

    Emerging data document that telomerase can directly regulate cancer-promoting pathways.

    “emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways.”

  • The paper relies on this without support.

    Telomerase expression in stem and progenitor cells is insufficient to maintain telomeres, particularly under stresses such as bone marrow transplantation or advancing age.

    “Telomerase expression in stem and progenitor cells appears to be insufficient to maintain telomeres, particularly with the stresses of bone marrow transplantation or with advancing age.”

  • The paper relies on this without support.

    Telomerase activity is regulated in large part at the level of TERT gene transcription.

    “Telomerase activity is regulated in large part at the level of TERT gene transcription”

  • The paper relies on this without support.

    The onset and severity of degenerative defects in telomerase-knockout mice track with the degree of telomere dysfunction.

    “The onset and severity of these defects tracked specifically with the degree of telomere dysfunction.”

  • The paper relies on this without support.

    The survival of telomerase-knockout mice is attributed to the much longer telomeres of laboratory mouse strains.

    “The survival of the mouse was attributed to the much longer telomeres of laboratory mouse strains.”

  • The paper relies on this without support.

    The difference in cellular trafficking between H/ACA snoRNAs and H/ACA scaRNAs is attributable to the CAB box.

    “The difference in cellular trafficking between the H/ACA snoRNAs and the H/ACA scaRNAs is attributable to the presence of another sequence motif, termed the Cajal body box or CAB box.”

  • The paper relies on this without support.

    Depletion of TCAB1 disrupts telomerase localization to Cajal bodies and leads to progressive telomere shortening.

    “Depletion of TCAB1 disrupts telomerase localization to Cajal bodies and leads to progressive telomere shortening.”

  • The paper relies on this without support.

    Potent oncogene combinations are highly inefficient at malignantly transforming cultured human cells.

    “However, similar cellular transformation experiments with potent oncogene combinations proved to be highly inefficient in the malignant transformation of cultured human cells.”

  • The paper relies on this without support.

    For most focal amplifications and deletions in human cancers, the relevant cancer genes are unknown.

    “At the same time, for the vast majority of such amplifications and deletions, the relevant cancer genes is not yet known for these loci so the question remains as to whether such loci contain driver cancer genes or are simply the by-product of genome instability and fragile sites.”

  • The paper relies on this without support.

    The gene targets of most CNAs in murine lymphomas are unknown.

    “However, and more strikingly, the gene target of these CNAs is not known in the vast majority of loci indicating that a large number of cancer genes remain to be discovered.”

  • The paper relies on this without support.

    In all cases of dyskeratosis congenita, telomeres are very short, typically below the first percentile of age-matched controls.

    “In all cases, telomeres in DC patients are very short, typically shorter than the first percentile of age-matched controls.”

  • The paper relies on this without support.

    Patients with dyskeratosis congenita are prone to myelodysplastic syndrome, and oral leukoplakia is a precursor lesion for invasive oral squamous cell carcinoma.

    “Patients with DC are prone to myelodysplastic syndrome, a preleukemic condition, and the oral leukoplakia is a precursor lesion for invasive squamous cell carcinoma of the oral mucosa.”
14 of 14

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Unlimited proliferation is the main means of acquiring oncogenic mutations and fixing successive genomic alterations that drive clonal expansion and cancer progression.

    “Unlimited proliferation is the main means of acquiring oncogenic mutations and fixing the successive genomic alterations that drive clonal expansion and cancer progression [345].”

    From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [345]

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Cited by

Sorted by citations

Authors
Artandi, S. E., & DePinho, R. A.
Affiliations
  • Stanford Medicine (US)
  • Harvard University (US)
Corresponding author
  • Artandi, S. E.
  • DePinho, R. A.
ORCID
Venue
Carcinogenesis
Publisher
Oxford University Press (OUP)
Published
2009-11-03
Volume
31
Issue
1
Pages
9-18
ISSN
  • 0143-3334 (ISSN-L)
  • 1460-2180
DOI
10.1093/carcin/bgp268
PMC
PMC3003493
OpenAlex
W2098085059
Cited by
823
References
77
Citations by year
2026: 11 · 2025: 27 · 2024: 39 · 2023: 21 · 2022: 30 · 2021: 45 · 2020: 37 · 2019: 50 · 2018: 43 · 2017: 63 · 2016: 77 · 2015: 79 · 2014: 58 · 2013: 65 · 2012: 72
FWCI
6.40
Type
journal article
Language
en
Open access
Locations
  • Carcinogenesis (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01CA084628)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
telomeres, telomerase, cancer, telomere dysfunction, telomere shortening, chromosomal instability, genomic instability, DNA damage checkpoint, aging, stem/progenitor cells, copy number alterations, translocation
MeSH terms
Animals, Humans, Neoplasms, Tumor Suppressor Protein p53, Telomere, Cellular Senescence, Germ-Line Mutation, Mice, Knockout, Telomerase, Dyskeratosis Congenita, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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