Telomeric function of mammalian telomerases at short telomeres

Fakhoury, Johans; Marie-Egyptienne, Delphine T.; Londoño-Vallejo, J. Arturo; Autexier, Chantal

doi:10.1242/jcs.063636

Cited by 15 publications

(24 citation statements)

References 69 publications

(138 reference statements)

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“…It is also plausible that telomerase activity could promote efficient repair following complete telomere loop excision in ALT cells, leading to a gain in efficiency of progression through specific phases of the cell cycle. Indeed, ALT-dependent homologous recombination resulted in heterogeneous telomeres within the cell population, and it has been previously shown that forced expression of human telomerase activity can limit the number of telomere DNA repeat signal-free ends in ALT cells (Fakhoury et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Fleisig

Wong

2011

Oncogene

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Constitutive telomerase activity maintains telomere length and confers immortal phenotypes to human cancers. The prevalence of telomerase, rather than a homologous recombination-based mechanism, in telomere length maintenance suggests that telomerase also has auxiliary roles in tumorigenesis. Here, we investigate growth advantages provided by the telomerase enzyme in oncogene-transformed human cells that do not require telomerase activity for telomere length control. Our data suggest that in oncogene-transformed cells, telomerase activity accelerates cell growth kinetics in a cell cycle phase-specific manner and promotes anchorage-independent growth. Coculture experiments demonstrated that this growth advantage conferred by telomerase activity is not due to increased cellular cross-talk. Growth advantages provided by telomerase required all functional aspects of the enzyme. Dissociation-of-activity-in-telomerase mutants and other functionally defective versions of telomerase were unable to promote oncogene-transformed cell growth, suggesting that canonical telomerase activities may be involved. We conclude that telomerase provides advantages to oncogene-transformed human cells, thereby supporting the development of telomerasebased anticancer chemotherapies targeting these growthpromoting effects.

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Section: Discussionmentioning

confidence: 99%

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Fleisig

Wong

2011

Oncogene

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“…The high tolerance of hTERT towards TR of different species was previously demonstrated using in vitro assays as well as in cellular systems [22,24,25,27]. We further investigated if vTR would be able to reconstitute telomerase activity in a cellular context (Fig.…”

Section: In Human Cells Vtr Is Not Able To Reconstitute a Functionalmentioning

confidence: 86%

“…Competitive RNA binding assays were performed according to previously described protocols [25]. The viral and human TRs were in vitro transcribed in the presence or absence of  32 P UTP.…”

Section: In Vitro Rna Binding Assaymentioning

confidence: 99%

“…More precisely, several studies demonstrated that hTERT can bind to heterologous vertebrate TRs, such as leporine TR and bovine TR, and those complexes respectively reconstitute telomerase activity in rabbit and bovine lens epithelial cells [22,24]. Interestingly, hTERT expression in murine TERT -/-embryonic stem cells in early passages is sufficient to prevent the signal-free ends and end-to-end fusions typically observed in mTERT -/-ES cells in late passages [25]. Conversely, mTERT cannot reconstitute or weakly reconstitutes telomerase activity in pig, chicken and human cells [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, mTERT cannot reconstitute or weakly reconstitutes telomerase activity in pig, chicken and human cells [25][26][27]. mTERT cannot promote the immortalization of primary human cells expressing the SV40 early region, nor can mTERT elongate the shortest telomeres in human cancer cells with alternative lengthening of telomeres (ALT) [25,26].…”

Section: Introductionmentioning

confidence: 99%

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The human telomerase catalytic subunit and viral telomerase RNA reconstitute a functional telomerase complex in a cell-free system, but not in human cells

Trapp-Fragnet¹,

Marie-Egyptienne²,

Fakhoury³

et al. 2012

Cellular and Molecular Biology Letters

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Abstract:The minimal vertebrate telomerase enzyme is composed of a protein component (telomerase reverse transcriptase, TERT) and an RNA component (telomerase RNA, TR). Expression of these two subunits is sufficient to reconstitute telomerase activity in vitro, while the formation of a holoenzyme comprising telomerase-associated proteins is necessary for proper telomere length maintenance. Previous reports demonstrated the high processivity of the human telomerase complex and the interspecies compatibility of human TERT (hTERT). In this study, we tested the function of the only known viral telomerase RNA subunit (vTR) in association with human telomerase, both in a cell-free system and in human cells. When vTR is assembled with hTERT in Unauthenticated Download Date | 5/10/18 10:16 AM CELLULAR & MOLECULAR BIOLOGY LETTERS 599 a cell-free environment, it is able to interact with hTERT and to reconstitute telomerase activity. However, in human cells, vTR does not reconstitute telomerase activity and could not be detected in the human telomerase complex, suggesting that vTR is not able to interact properly with the proteins constituting the human telomerase holoenzyme.

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Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson‐Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform

Bikkul

Faragher

Worthington

et al. 2019

Genes Chromosomes & Cancer

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Immortalizing primary cells with human telomerase reverse transcriptase (hTERT) has been common practice to enable primary cells to be of extended use in the laboratory because they avoid replicative senescence. Studying exogenously expressed hTERT in cells also affords scientists models of early carcinogenesis and telomere behavior. Control and the premature ageing disease—Hutchinson‐Gilford progeria syndrome (HGPS) primary dermal fibroblasts, with and without the classical G608G mutation have been immortalized with exogenous hTERT. However, hTERT immortalization surprisingly elicits genome reorganization not only in disease cells but also in the normal control cells, such that whole chromosome territories normally located at the nuclear periphery in proliferating fibroblasts become mislocalized in the nuclear interior. This includes chromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS cells, which physically express an isoform of the LINC complex protein SUN1 that has previously only been theoretical. Additionally, this HGPS cell line has also become genomically unstable and has a tetraploid karyotype, which could be due to the novel SUN1 isoform. Long‐term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of telomere length in the immortalized cells and resulted that these mislocalized internal chromosomes to be located at the nuclear periphery, as assessed in actively proliferating cells. Taken together, these findings reveal that elongated telomeres lead to dramatic chromosome mislocalization, which can be restored with a drug treatment that results in telomere reshortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when interpreting data from genomic studies in hTERT‐immortalized cell lines.

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Telomeric function of mammalian telomerases at short telomeres

Cited by 15 publications

References 69 publications

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

Telomerase promotes efficient cell cycle kinetics and confers growth advantage to telomerase-negative transformed human cells

The human telomerase catalytic subunit and viral telomerase RNA reconstitute a functional telomerase complex in a cell-free system, but not in human cells

Telomere elongation through hTERT immortalization leads to chromosome repositioning in control cells and genomic instability in Hutchinson‐Gilford progeria syndrome fibroblasts, expressing a novel SUN1 isoform

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