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Review
. 2022 Sep 20;10(10):2335.
doi: 10.3390/biomedicines10102335.

Telomeres and Telomerase in the Control of Stem Cells

Alexey Yu Lupatov  1 , Konstantin N Yarygin  1
Affiliations
Review

Telomeres and Telomerase in the Control of Stem Cells

Alexey Yu Lupatov et al. Biomedicines. .

Abstract

Stem cells serve as a source of cellular material in embryogenesis and postnatal growth and regeneration. This requires significant proliferative potential ensured by sufficient telomere length. Telomere attrition in the stem cells and their niche cells can result in the exhaustion of the regenerative potential of high-turnover organs, causing or contributing to the onset of age-related diseases. In this review, stem cells are examined in the context of the current telomere-centric theory of cell aging, which assumes that telomere shortening depends not just on the number of cell doublings (mitotic clock) but also on the influence of various internal and external factors. The influence of the telomerase and telomere length on the functional activity of different stem cell types, as well as on their aging and prospects of use in cell therapy applications, is discussed.

Keywords: aging; cell senescence; replicative lifespan; stem cells; telomerase; telomeres.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The problem of incomplete DNA replication and its solution by “primitive” organisms. (A) Incomplete replication of the 3′ end of DNA in eukaryotic cells. Replicons located in the telomere region cannot displace the last RNA primer of the lagging strand. (B) A covalently closed circular genome replication. In theta replication (prokaryotes, viruses), the last RNA primer of the lagging strand is replaced by the leading strand. A rolling cycle mechanism (viruses, plasmids) uses a single-stranded nick as a primer for DNA synthesis. As a result, a concatemer containing several complete genome copies is formed. (C) Hepadnaviruses do not have a covalently closed circular genome, but it can be easily restored by reparative DNA synthesis after cell infection. Despite this, the virus uses reverse transcription as a strategy for its genome replication. Whole genome RNA, after its translation, is used as a template for minus DNA strand synthesis. Reverse transcriptase (RT) includes a domain that can prime DNA synthesis from a tyrosine residue. The incomplete plus DNA strand is synthesized by DNA polymerase primed with the rest of the degraded whole genome RNA. (D) Parvoviruses use hairpins at the ends of their DNA (rabbit ears) as primers for DNA polymerase. (E) Adenovirus DNA polymerase forms a complex with a terminal protein (TP) that can act as a primer for unidirectional DNA replication.
Figure 2
Figure 2
The main players of telomere stabilization and elongation. Shelterin contains six proteins that stabilize chromosome ends, prevent activation of the DNA damage response (DDR) system, and suppress telomerase-dependent telomere elongation. In the absence of fully assembled shelterin, telomerase-mediated lengthening of telomeres becomes possible and proceeds via the binding of TERT to TERC stabilized by the dyskerin complex (dyskerin, NOP10, NHP2, GAR1). TERT can also exhibit non-canonical activity by modulating gene expression to protect against cell death following double-stranded DNA damage and protect mitochondria from ROS.
Figure 3
Figure 3
Telomere theory of aging; state of the art.
Figure 4
Figure 4
Telomere length dynamics in various types of stem cells.
See this image and copyright information in PMC

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