Tieing together loose ends: telomere instability in cancer and aging

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.

Telomere length and TERT polymorphisms as biomarkers in asbestos-related diseases

“…Previous studies stated that the telomeres in cancer patients are shorter but sta-ble when compared to healthy individuals. 18,20,21 Also, a study analysing telomere length in pleural effusion cells reported shorter telomeres in 12 MM patients compared to 35 cases with non-neoplastic disease. 23 Interestingly, older patients with MM had longer telomeres than younger patients with MM.…”

“…[15][16][17][18] The regulation of the expression of the human telomerase reverse transcriptase (hTERT) subunit of telomerase occurs predominantly at the transcriptional level. [19][20][21] Numerous single nucleotide polymorphisms (SNP) in the hTERT gene may also have an impact on telomerase expression levels and activity, and may thus play a role in the risk of carcenogenesis, as well as the prognosis and survival of cancer patients. 18,19,22 Telomere length is influenced by cellular senescence, chronic inflammation and oxidative stress.…”

“…7,18 Cancer cells exhibit shorter, yet stable, telomeres compared to non-neoplastic cells. 18,20,21 Malignant mesothelioma is considered to be a telomerase dependant cancer. 22 The impact of asbestos exposure on telomere length was also established in pleural effusion cells, showing that non-neoplastic cells had longer telomeres than neoplastic MM cells and that telomere shortening and genomic instability play significant roles in MM pathogenesis, and may also serve as biomarkers for disease development, treatment response, and prognosis.…”

The role of aging in cancer

“…On the other hand, dysfunctional telomeres, reminiscent of DNA double‐strand breaks, can also promote genome DNA recombination events, genome instability, and cancer [60]. Lea Harrington and colleagues discuss this dual role of telomeres in aging and cancer, including as targets for therapeutic interventions and potential cross‐over of healthy aging interventions and cancer prevention [61].…”

Arabidopsis AN3 and OLIGOCELLULA genes link telomere maintenance mechanisms with cell division and expansion control

“…Mutations in chromosome capping proteins or critical shortening of telomeric DNA tracts can lead to an increased incidence of end-to-end chromosome fusions and genome aberrations (Borges et al 2022;Song et al 2008). To check if telomere integrity is compromised in an3 and oli mutants, we performed cytogenetic analysis of mitotically dividing cells in pistils.…”