Severe growth defect in mouse cells lacking the telomerase RNA component
Abstract
The ribonucleoprotein enzyme telomerase synthesizes telomeric DNA onto chromosome ends. Telomere length is maintained, by the presence of telomerase activity, in the vast majority of primary tumours and stem cells, suggesting that telomere maintenance is essential for cellular immortalization. Recently, the telomerase RNA component in human and mouse (TERC and Terc, respectively), a telomerase-associated protein TEP1/TLP1 (refs 6,7) and the human catalytic subunit protein TERT (refs 8,9) have been identified. To examine the role of telomerase in telomere maintenance and cellular viability, we established Terc-deficient embryonic stem (ES) cells. It is known that telomerase activity is absent in cells from Terc-knockout mice. Although the study showed that telomere shortening was observed in the Terc-deficient cells from first to six generation animals, whether telomerase-dependent telomere maintenance was essential for cellular viability remained to be elucidated. To address this issue, we examined Terc-deficient ES cells under long-term culture conditions. Accompanying the continual telomere shortening, the growth rate of Terc-deficient ES cells was gradually reduced after more than 300 divisions. An impaired growth rate was maintained to approximately 450 divisions, and then cell growth virtually stopped. These data clearly show that telomerase-dependent telomere maintenance is critical for the growth of mammalian cells.
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Due to the very long telomeres of Mus musculus, critical reduction in telomere length and chromosomal instability is only seen following extensive passage of mTR−/− cells, after successive generations of mTR−/− mice, or in aged mTR−/− organs with high proliferative histories.
“Due to the very long telomeres of Mus musculus, critical reduction in telomere length and chromosomal instability is only seen following extensive passage of mTR−/− cells (Niida et al. 1998”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Niida et al. 1998
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“The genetic ablation or mutation of the essential RNA component of telomerase (Singer and Gottschling, 1994; Ahmed et al., 1998; Niida et al., 1998) or inhibition of telomerase by small molecules (Herbert et al., 1999) in these cells results in the gradual reduction of the average telomere length…”
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“Interestingly, telomerase knockout mice (TR –/–) over a multigenerational time scale eventually lose significant telomere sequence (note that the lab mouse has very large telomere arrays, up to 200 kb) resulting in increased chromosome rearrangements and development of problems with lymphoproliferative cells, germ cel…”
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- Authors
- Niida, H., Matsumoto, T., Satoh, H., Shiwa, M., Tokutake, Y., Furuichi, Y., & Shinkai, Y.
- Affiliations
- Roche (Japan) (JP)
- Kyoto University (JP)
- Venue
- Nature Genetics
- Published
- 1998-06
- Volume
- 19
- Issue
- 2
- Pages
- 203-206
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/580
- OpenAlex
- W98533868
- Cited by
- 156
- References
- 27
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 4 · 2014: 2 · 2013: 5 · 2012: 4
- FWCI
- 11.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- telomerase, telomerase RNA, telomere maintenance, telomere shortening, embryonic stem cells, cell immortalization, telomerase reverse transcriptase, cell proliferation
- MeSH terms
- Animals, Cell Division, Cells, Cultured, DNA-Binding Proteins, Humans, Proteins, RNA, Stem Cells, Restriction Mapping, Telomere, In Situ Hybridization, Fluorescence, Mice, Knockout, Telomerase, RNA, Untranslated, Mice, RNA, Long Noncoding
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