PubMed · 11516661
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S K Evans. 2001-06-05. Telomeres.. https://doi.org/10.1016/s0960-9822(01)00249-4
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Telomerase plays an important role in sustaining eukaryotic linear chromosomes, as elongation of telomeres is needed to counterbalance the shortening occurring in each replication round. Nevertheless, in telomerase-deficient cells, Alternative Lengthening of Telomeres (ALT) pathways can maintain telomeres by employing recombination-based mechanisms. In the budding yeast Naumovozyma castellii, effective activation of the ALT pathway leads to bypass of senescence and supports long-term growth. We found that telomere structures in N. castellii ALT cells are stably maintained at a shortened uniform length over extensive numbers of generations. This is correlated to the spreading of a subtelomeric sequence, TelKO element, to all telomeres. Genome sequencing of the wild-type strain revealed variants of the TelKO element, differing in their lengths, and separate ALT strains are maintained by spreading of distinct TelKO element variants. Although short uniform telomere structures are predominant, sporadic telomere lengthening events occur by addition of long repeated arrays of TelKO elements. The telomere-binding protein Rap1 can bind to TelKO sequences in vitro, indicating a functional role of TelKO elements in providing stability to shortened ALT telomeres. Our results suggest that stable maintenance and telomere functionality may be achieved by incorporating the distal subtelomeric TelKO sequences into the telomeric chromatin cap.
Telomerase reverse transcriptase (TERT), the catalytic enzyme component of telomerase, plays multiple roles in cellular biology. Its canonical function is primarily associated with telomere maintenance and genomic stability. In addition, several studies revealed critical non-canonical extra-telomeric functions of TERT in various cellular processes, including cell proliferation and survival, DNA damage response, transcription, signal transduction, and metabolic regulation, both in normal and in cancer cells. Notably, TERT is aberrantly upregulated in more than 80% of hepatocellular carcinoma (HCC) cases, making it an important target in liver cancer research. However, due to the diversity and complexity of TERT's functions in vivo, the precise mechanisms by which TERT contributes to the initiation and progression of HCC remain unclear. A recent study published in The Journal of Pathology using the Alb-Cre;TertTg mouse model and clinical HCC samples addresses the role of TERT in hepatocarcinogenesis. The study demonstrates that TERT promotes cell cycle progression and hepatocarcinogenesis by enhancing NF-κB promoter activity and facilitating the ubiquitination of p21. Notably, absence of functional p53 accelerates liver tumor development in TERT transgenic mice. These findings further underscore the critical role of TERT in inflammation-driven hepatocarcinogenesis and provide new insights into its underlying mechanisms. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Telomeres are DNA and protein structures that form complexes protecting the ends of chromosomes. Understanding of the mechanisms maintaining telomeres and insights into their function have advanced considerably in recent years. This review summarizes the currently known components of the telomere/telomerase functional complex, and focuses on how they act in the control of processes occurring at telomeres. These include processes acting on the telomeric DNA and on telomeric proteins. Key among them are DNA replication and elongation of one telomeric DNA strand by telomerase. In some situations, homologous recombination of telomeric and subtelomeric DNA is induced. All these processes act to replenish or restore telomeres. Conversely, degradative processes that shorten telomeric DNA, and nonhomologous end-joining of telomeric DNA, can lead to loss of telomere function and genomic instability. Hence they too must normally be tightly controlled.