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Review
. 2022 Sep;16(18):3380-3396.
doi: 10.1002/1878-0261.13299. Epub 2022 Aug 16.

Tieing together loose ends: telomere instability in cancer and aging

Gustavo Borges  1 , Mélanie Criqui  1 , Lea Harrington  1   2
Affiliations
Review

Tieing together loose ends: telomere instability in cancer and aging

Gustavo Borges et al. Mol Oncol. 2022 Sep.

Abstract

Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.

Keywords: aging; cancer; genome instability; senescence; telomerase reverse transcriptases; telomeres.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Overview of mammalian telomere structure. (A) Schematic representation of the chromosome end, or telomere in mammals. Telomeric DNA is composed of the hexanucleotide sequence TTAGGG with a single stranded G‐rich 3′ overhang that is looped back into the telomeric DNA to form a telomeric loop (T‐loop). The shelterin complex (composed of the proteins TRF1, TRF2, TIN2, RAP1, TPP1 and POT1) protects telomeres from being recognized as a DNA double‐stranded break. (B) During the S‐phase of the cell cycle, the T‐loop is opened and the G‐rich strand becomes accessible for extension by telomerase. After telomerase has extended the G‐rich strand, the CST complex (composed of the subunits CTC1, STN1, TEN1) together with the DNA replication machinery carries out fill‐in DNA synthesis of the complimentary C‐rich strand. (C) Critically short telomeres exhibit defects not only in telomere integrity (due to a DNA damage response) but can also perturb the epigenetic state (reducing CpG methylation and increasing Nanog expression). [Colour figure can be viewed at wileyonlinelibrary.com]
Fig. 2
Fig. 2
Consequences of telomere shortening. (A) Senescence is referred to as an irreversible exit from the cell cycle. This state can occur via a variety of mechanisms that include eroded telomeres. When telomeres reach a critically short threshold, cells undergo telomere‐induced (or replicative) senescence, which is triggered by p53 and its downstream effector p21, a cyclin‐dependent kinase inhibitor that arrests the cell cycle. Senescent cells can secrete factors that modify neighbouring tissues and cells and enhance aging, via a process termed the senescence‐associated secretory phenotype (SASP). (B) If a cell bypasses senescence and continues to divide, telomere fusions can occur, leading to a cycle of chromosome breakage‐fusion‐bridge formation and genetic instability. (C) Epigenetic modifications are also linked to telomere shortening. Such modifications can influence transcriptional activity and cell fate. In the left image, DNA wrapped around the histones (represented by the green spheres) may contain extensive post‐translational modifications (red sphere) on the histone tail, and the DNA itself can be methylated (small black sphere). Murine embryonic stem cells are particularly sensitive to epigenetic modifications driven by telomere shortening, which can reduce stem cell renewal potential (middle image). Telomere shortening can also affect the ability of stem cells to maintain a functional pluripotent state and/or differentiated state (right image). [Colour figure can be viewed at wileyonlinelibrary.com]
Fig. 3
Fig. 3
Current and emerging telomere‐targeting treatments. (A) Therapeutic strategies that target telomerase use compounds (such as Imetelstat and BIBR1532) that can directly inhibit the catalytic core of the telomerase enzyme, or they may also affect telomere DNA replication (such as the nucleotide analogue AZT or the nucleoside analogue 6‐thio‐dG). The telomeric DNA sequence is indicated (TTAGGG repeats in the 5′ to 3′ direction). Telomerase is a multi‐subunit complex that contains TERT (orange), the telomerase RNA (hTR), and associated subunits (GAR, NOP10, NHP2, and dyskerin). For simplicity only 1 telomeric repeat of the hTR template motif is shown; the full template contains 1.5 telomeric repeats (CAAUCCCAAUC) that is reverse‐transcribed in an iterative process. (B) More recently, compounds that affect telomere structure, such as G‐quadraplex (G4) stabilizers, have been investigated, as they induce immediate cell death upon telomere uncapping and do not exhibit a therapeutic lag, as is the case with telomere attrition. The telomeric G‐quadruplexes are located at the 3′ end of the G‐rich strand. The yellow circle represents the G4‐stabilizers as indicated. (C) As the expression of TERT is regulated by DNA methylation status (through the THOR region), chromatin‐modifying agents might also have therapeutic benefit in the treatment of telomerase‐positive tumours. THOR stands for TERT Hypermethylated Oncological Region. Red spheres indicate methylated CpG dinucleotides at the THOR region that may be a potential target site for the use of hypomethylating agents. TPM indicates the promoter region where the TERT promoter mutations are commonly found, upstream of the coding sequence (TERT CDS). [Colour figure can be viewed at wileyonlinelibrary.com]
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